Abstract

Several studies now provide evidence of ketamine hydrochloride's ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness.

Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressantsPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAGoldstein-Piekarski, A. N., Korgaonkar, M. S., Green, E., Suppes, T., Schatzberg, A. F., Hastie, T., Nemeroff, C. B., Williams, L. M.2016; 113 (42): 11955-11960

Abstract

Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.

Abstract

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance and a potential role of HPA axis genetic variation in cognition. The present study investigated the simultaneous roles HPA axis activity, clinical symptomatology and HPA genetic variation play in cognitive performance. Patients with major depression with psychotic major depression (PMD) and with nonpsychotic major depression (NPMD) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, overnight hourly blood sampling for cortisol and genetic assessment. Cognitive performance differed as a function of depression subtype. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher cortisol than did NPMDs and HCs. Cortisol, clinical symptoms and variation in genes, NR3C1 (glucocorticoid receptor; GR) and NR3C2 (mineralocorticoid receptor; MR) that encode for GRs and MRs, predicted cognitive performance. Beyond the effects of cortisol, demographics and clinical symptoms, NR3C1 variation predicted attention and working memory, whereas NR3C2 polymorphisms predicted memory performance. These findings parallel the distribution of GR and MR in primate brain and their putative roles in specific cognitive tasks. HPA axis genetic variation and activity were important predictors of cognition across the entire sample of depressed subjects and HR. GR and MR genetic variation predicted unique cognitive functions, beyond the influence of cortisol and clinical symptoms. GR genetic variation was implicated in attention and working memory, whereas MR was implicated in verbal memory.Molecular Psychiatry advance online publication, 16 August 2016; doi:10.1038/mp.2016.120.

Abstract

The need for innovative methods to promote training, advancement, and retention of clinical and translational investigators in order to build a pipeline of trainees to focus on mental health-relevant research careers is pressing. The specific aim of the Career Development Institute for Psychiatry is to provide the necessary skill set and support to a nationally selected broad-based group of young psychiatrists and PhD researchers to launch and maintain successful research careers in academic psychiatry. The program targets such career skills as writing, negotiating, time management, juggling multiple demanding responsibilities, networking, project management, responsible conduct of research, and career goal setting. The current program builds on the previous program by adding a longitudinal, long-distance, virtual mentoring, and training program, seen as integral components to sustaining these career skills.Career development activities occur in four phases over a 24-month period for each annual class of up to 18 participants: online baseline career and skills self-assessment and goal setting, preparations for 4-day in-person workshop, long-distance structured mentoring and online continued learning, peer-mentoring activities, and post-program career progress and process evaluation. Program instructors and mentors consist of faculty from the University of Pittsburgh and Stanford University as well as successful past program graduates from other universities as peer mentors. A comprehensive website facilitates long-distance activities to occur online. Continued training occurs via webinars every other month by experts discussing topics selected for the needs of each particular class. Personally assigned mentors meet individually bimonthly with participants via a secure web-based "mentor center" that allows mentor dyads to collaborate, share, review, and discuss career goals and research activities.Preliminary results after the first 24 months are favorable. Almost uniformly, participants felt the program was very helpful. They had regular contact with their long-distance mentor at least every 2 months over the 2-year period. At the end of the 2-year period, the majority of participants had full-time faculty appointments with K-award support and very few were doing primarily clinical work.The longitudinal program of education, training, mentoring, peer support, and communications for individuals making the transition to academic research should increase the number of scientists committed to research careers in mental health.

Abstract

Anhedonia, the reduced ability to experience pleasure in response to otherwise rewarding stimuli, is a core symptom of major depressive disorder (MDD). Although the posterior ventromedial prefrontal cortex (pVMPFC) and its functional connections have been consistently implicated in MDD, their roles in anhedonia remain poorly understood. Furthermore, it is unknown whether anhedonia is primarily associated with intrinsic 'resting-state' pVMPFC functional connectivity or an inability to modulate connectivity in a context-specific manner. To address these gaps, a pVMPFC region of interest was first identified using activation likelihood estimation meta-analysis. pVMPFC connectivity was then examined in relation to anhedonia and general distress symptoms of depression, using both resting-state and task-based functional magnetic resonance imaging involving pleasant music, in current MDD and healthy control groups. In MDD, pVMPFC connectivity was negatively correlated with anhedonia but not general distress during music listening in key reward- and emotion-processing regions, including nucleus accumbens, ventral tegmental area/substantia nigra, orbitofrontal cortex and insula, as well as fronto-temporal regions involved in tracking complex sound sequences, including middle temporal gyrus and inferior frontal gyrus. No such dissociations were observed in the healthy controls, and resting-state pVMPFC connectivity did not dissociate anhedonia from general distress in either group. Our findings demonstrate that anhedonia in MDD is associated with context-specific deficits in pVMPFC connectivity with the mesolimbic reward system when encountering pleasurable stimuli, rather than a static deficit in intrinsic resting-state connectivity. Critically, identification of functional circuits associated with anhedonia better characterizes MDD heterogeneity and may help track of one of its core symptoms.

Abstract

Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

Abstract

Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping with gains in subsequent emotion regulation. Here we investigate the effects of learning to cope with stress on anterior cingulate cortex gene expression in monkeys and mice. Anterior cingulate cortex is involved in learning, memory, cognitive control, and emotion regulation. Monkeys and mice were randomized to either stress coping or no-stress treatment conditions. Profiles of gene expression were acquired with HumanHT-12v4.0 Expression BeadChip arrays adapted for monkeys. Three genes identified in monkeys by arrays were then assessed in mice by quantitative real-time polymerase chain reaction. Expression of a key gene (PEMT) involved in acetylcholine biosynthesis was increased in monkeys by coping but this result was not verified in mice. Another gene (SPRY2) that encodes a negative regulator of neurotrophic factor signaling was decreased in monkeys by coping but this result was only partly verified in mice. The CACNG2 gene that encodes stargazin (also called TARP gamma-2) was increased by coping in monkeys as well as mice randomized to coping with or without subsequent behavioral tests of emotionality. As evidence of coping effects distinct from repeated stress exposures per se, increased stargazin expression induced by coping correlated with diminished emotionality in mice. Stargazin modulates glutamate receptor signaling and plays a role in synaptic plasticity. Molecular mechanisms of synaptic plasticity that mediate learning and memory in the context of coping with stress may provide novel targets for new treatments of disorders in human mental health.

Abstract

Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

Abstract

Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.Molecular Psychiatry advance online publication, 21 October 2014; doi:10.1038/mp.2014.137.

Abstract

Ketamine is a psychoactive anesthetic agent, which has been approved and utilized for various forms of anesthesia over decades. Recently, ketamine has been demonstrated to have robust and rapid antidepressant effects in individuals with treatment-resistant depression. After more than a decade of research, it is unclear what the mechanisms underlying the novel antidepressant effect are. The consensus has centered on NMDA properties of ketamine as a potential factor in the mechanism for antidepressant action. However, this may be a true but partial explanation of the effects of ketamine as a novel antidepressant. It appears that ketamine influences synaptic plasticity and may promote new synapse formation. From a neurocircuitry perspective, ketamine may exert some of its effects on the anterior cingulate.

Abstract

Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time.Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing.This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward.ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.

Abstract

Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

Abstract

Current treatments for smoking cessation have limited efficacy. A potential pharmaceutical treatment for smoking cessation is selegiline, a selective and irreversible monoamine oxidase B inhibitor. A few clinical trials have been carried out using selegiline but the results have been mixed. We sought to determine if genetic markers in cholinergic loci in the 15q24 chromosomal region predict response to smoking cessation therapy with selegiline.We performed an 8-week double-blind, placebo-controlled clinical trial of the selegiline transdermal system (STS) in heavy smokers, with follow-up at weeks 25 and 52. Eight single nucleotide polymorphisms (SNPs) in the 15q24 region, which contains the genes for the nicotinic acetylcholine receptor subunits CHRNA5, CHRNA3, and CHRNB4, were investigated for association with treatment response.The CHRNB4 promoter SNP rs3813567 was associated with both point prevalence abstinence (PPA) and post-quit craving. Carriers of the minor C allele treated with selegiline showed lower rates of abstinence and higher levels of craving than selegiline-treated non-carriers, indicating that the rs3813567 C allele adversely affects abstinence in selegiline-treated smokers. This effect was not present among placebo-treated smokers. Selegiline-treated smokers with the CHRNA5 rs680244 GG genotype had lower post-quit craving, and unlike placebo-treated GG-carrying smokers, did not experience a post-quit increase in depressive symptoms.Variants in genes encoding cholinergic receptors affect abstinence, craving and mood in selegiline-treated smokers. Selegiline primarily affects dopamine levels in the brain, but cholinergic input affects nicotine-induced dopaminergic activity. These markers may have value in identifying those likely to respond to selegiline for smoking cessation.

Abstract

The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications.Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report).Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect.There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.

Abstract

The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

Abstract

The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.

Abstract

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.

Abstract

Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception.MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history.Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity.Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task.Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior.

Abstract

Depression involves impairments in a range of cognitive and emotional capacities. It is unknown whether these functions can inform medication choice when considered as a composite predictive biomarker. We tested whether behavioral tests, grounded in the neurobiology of cognitive and emotional functions, predict outcome with common antidepressants. Medication-free outpatients with nonpsychotic major depressive disorder (N=1008; 665 completers) were assessed before treatment using 13 computerized tests of psychomotor, executive, memory-attention, processing speed, inhibitory, and emotional functions. Matched healthy controls (N=336) provided a normative reference sample for test performance. Depressed participants were then randomized to escitalopram, sertraline, or venlafaxine-extended release, and were assessed using the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) and the 17-item Hamilton Rating Scale for Depression. Given the heterogeneity of depression, analyses were furthermore stratified by pretreatment performance. We then used pattern classification with cross-validation to determine individual patient-level composite predictive biomarkers of antidepressant outcome based on test performance. A subgroup of depressed participants (approximately one-quarter of patients) were found to be impaired across most cognitive tests relative to the healthy norm, from which they could be discriminated with 91% accuracy. These patients with generally impaired cognitive task performance had poorer treatment outcomes. For this impaired subgroup, task performance furthermore predicted remission on the QIDS-SR16 at 72% accuracy specifically following treatment with escitalopram but not the other medications. Therefore, tests of cognitive and emotional functions can form a clinically meaningful composite biomarker that may help drive general treatment outcome prediction for optimal treatment selection in depression, particularly for escitalopram.

Abstract

Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

Abstract

There is increasing interest in using neurobiological measures to inform psychiatric nosology. It is unclear at the present time whether anxiety and depression are neurobiologically distinct or similar processes. It is also unknown if the best way to examine these disorders neurobiologically is by contrasting categorical definitions or by examining symptom dimensions.A cross-sectional neuroimaging study was conducted of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), comorbid GAD and MDD (GAD/MDD), or neither GAD nor MDD (control subjects). There were 90 participants, all medication-free (17 GAD, 12 MDD, 23 GAD/MDD, and 38 control subjects). Diagnosis/category and dimensions/symptoms were assessed to determine the best fit for neurobiological data. Symptoms included general distress, common to anxiety and depression, and anxiety-specific (anxious arousal) or depression-specific (anhedonia) symptoms. Low-frequency (.008-.1 Hz) signal amplitude and functional connectivity analyses of resting-state functional magnetic resonance imaging data focused on a priori cortical and subcortical regions of interest.Support was found for effects of diagnosis above and beyond effects related to symptom levels as well as for effects of symptom levels above and beyond effects of diagnostic categories. The specific dimensional factors of general distress and anxious arousal as well as a diagnosis of MDD explained unique proportions of variance in signal amplitude or functional connectivity.Using resting-state functional magnetic resonance imaging, our data show that a single conceptual model alone (i.e., categorical diagnoses or symptom dimensions) provides an incomplete mapping of psychopathology to neurobiology. Instead, the data support an additive model that best captures abnormal neural patterns in patients with anxiety and depression.

Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Abstract

We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.

Abstract

Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

Abstract

To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.

Abstract

Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P<0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.

Abstract

Stress inoculation entails intermittent exposure to mildly stressful situations that present opportunities to learn, practice and improve coping in the context of exposure psychotherapies and resiliency training. Here we investigate behavioral and hormonal aspects of stress inoculation modeled in mice. Mice randomized to stress inoculation or a control treatment condition were assessed for corticosterone stress hormone responses and behavior during open-field, object-exploration and tail-suspension tests. Stress inoculation training sessions that acutely increased plasma levels of corticosterone diminished subsequent immobility as a measure of behavioral despair on tail-suspension tests. Stress inoculation also decreased subsequent freezing in the open field despite comparable levels of thigmotaxis in mice from both treatment conditions. Stress inoculation subsequently decreased novel-object exploration latencies and reduced corticosterone responses to repeated restraint. These results demonstrate that stress inoculation acutely stimulates glucocorticoid signaling and then enhances subsequent indications of active coping behavior in mice. Unlike mouse models that screen for the absence of vulnerability to stress or presence of traits that occur in resilient individuals, stress inoculation training reflects an experience-dependent learning-like process that resembles interventions designed to build resilience in humans. Mouse models of stress inoculation may provide novel insights for new preventive strategies or therapeutic treatments of human psychiatric disorders that are triggered and exacerbated by stressful life events.

Abstract

The development of new antidepressants has had mixed results over the past decade, with several notable failures. This paper reviews a number of major initiatives in the development of new antidepressant agents. Traditional strategies to build on agents that have monoaminergic effects at the synapse (e.g., vilazodone and ketamine) have been complemented with efforts that have emphasized devices and brain circuits (e.g., deep brain stimulation and transcranial magnetic stimulation) or chemical agents that modulate neuroendocrine systems (e.g., glucocorticoid antagonists, mixed melatonin agonists/serotonin type-2 receptor antagonists). Interestingly, chemical agents, such as onabotulinumtoxin A, may affect brain circuits as well. We present data from recent studies in drug and device development--reviewing progress made, stumbling blocks encountered, and issues that need to be addressed in future studies.

Abstract

This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress.Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress.Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants.Due to the cross-sectional nature of this study, causal pathways cannot be concluded.Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.

Anna-Monika Award Lecture, DGPPN Kongress, 2013: The role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis of psychotic major depressionWORLD JOURNAL OF BIOLOGICAL PSYCHIATRYSchatzberg, A. F.2015; 16 (1): 2-11

Abstract

This Anna Monika Award Lecture updates the role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis and treatment of psychotic major depression (PMD).Published reports from our group and others on the clinical phenomenology (including cognition), HPA axis activity, and genetics of PMD are reviewed as are published trials of the GR antagonist, mifepristone.Current prevalence of PMD is 0.4%. PMD patients demonstrate significant elevations in HPA activity (e.g., particularly high rates of dexamethasone non-suppression, high post-dexamethasone cortisol, etc.) as well as significant impairment in cognition (attention, executive function/response inhibition and verbal and visual memory). High cortisol levels correlate with a number of cognitive deficits (e.g., verbal memory). Allelic variants of the glucocorticoid receptor (GR) gene contribute significantly to both cortisol levels and to measures of psychosis; corticotropin-releasing hormone receptor 1 variants contribute to measures of depression and psychosis. GR antagonists have produced rapid improvement in psychotic symptoms, although failed trials indicate a therapeutic blood level that may require a dose of 1,200 mg/day that is much higher than the commonly tested 600 mg/day.HPA axis over-activity appears to play a major role in the pathogenesis of PMD and is a target of drug development.

Abstract

Our objective is to compare legal difficulties that psychiatrists encounter in regulatory agency and malpractice (insurance) settings.Data sources included a literature search of malpractice and medical board discipline from 1990 to 2009 (rates and types of discipline); publicly available insurance data (malpractice frequency and type); and data from the National Practitioner Data Bank (NPDB) (required reports of malpractice settlements and hospital discipline).Medical board discipline findings indicate that psychiatrists are at increased risk of disciplinary action compared with other specialties. NPDB data indicated relatively infrequent problems for psychiatrists. In malpractice, psychiatry accounted for a small percentage of overall claims and settlements. Overall, more years in practice and a lack of board certification increased the risk of legal difficulties.There are shared and separate risk factors in the malpractice and regulatory agency areas, but there is evidence that these 2 legal areas are distinct from each other.

Abstract

Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.

Abstract

Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.Molecular Psychiatry advance online publication, 29 October 2013; doi:10.1038/mp.2013.129.

Abstract

This study expands on previous research by examining the effects of prolonged grief disorder (PGD) symptoms and bereavement on diurnal cortisol patterns above and beyond depressive symptomatology.Drawing on information from 56 depressed older adults, 3 groups were compared: (1) a depressed nonbereaved group, (2) a depressed bereaved without elevated PGD symptoms group, and (3) a depressed bereaved with elevated PGD symptoms group. Multilevel modeling was used to examine differences in diurnal cortisol profiles between these 3 groups, controlling for demographic factors and depressive symptoms.Results revealed that those who were bereaved had more dysregulated cortisol patterns, but PGD symptomatology seemed to have little effect. Subsidiary analysis with just the bereaved participants suggests that those who were recently widowed may have had greater cortisol dysregulation compared with other bereaved individuals in the sample.These findings suggest that the circumstance of being bereaved may be associated with more dysregulated cortisol, regardless of PGD symptomatology. This pattern of results might reflect greater disturbance in daily routines among bereaved individuals and acute stress in the case of those experiencing the recent loss of a spouse, which leads to disruption in circadian rhythms and the diurnal cycle of cortisol.

Abstract

Previous studies suggest that individuals with elevated levels of cortisol (the "stress hormone") could be particularly resistant to treatment for depression. However, most of these studies have been conducted in the context of antidepressant medications, and no study has examined pretreatment cortisol levels as a predictor of treatment outcomes among older adults with depression in cognitive-behavioral therapy (CBT), despite the relevance of this population for such a research question. The current study includes 54 older adults with depression who provided salivary cortisol samples at baseline and completed measures of depression at pretreatment and posttreatment, following a 12-week course of CBT. Structural equation modeling results suggest that those with higher daily outputs of cortisol and flatter diurnal slopes were less likely to benefit from CBT-a finding which if replicated could have important implications for clinical practice and future research.

Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Abstract

Glutamatergic therapies are emerging as the new path for the treatment of Major Depression Disorder. Recent reports reviewing the use of glutamate activity modulators in the treatment of resistant depression advocate the importance of understanding the alterations of the diverse components of this complex system in mood disorders. In this postmortem study we used in situ hybridization and microarray analysis to evaluate the gene expression of the membrane transporters SLC1A2 and SLCA3 and the vesicular transporter SLCA17A7 in the hippocampus of Major Depressive Disorder (MDD) and Bipolar Disorder (BPD) subjects. Samples from 8 controls, 11 MDD and 6 BPD subjects were processed for in situ hybridization using cRNA probes for SLC1A2, SLC1A3 and SLC17A7. Laser capture microdissection was used to collect tissue from adjacent sections for microarray analysis. The results showed that the expression of the membrane transporters SLC1A2 and SLC1A3 was diminished in the MDD group compared to controls. The expression of the vesicular glutamate transporter SLC17A7 on the other hand was increased in MDD subjects. As for the BPD group, all three transporters showed trends similar to those observed in MDD, but the changes observed did not reach significance. We hypothesize that the decreased expression of the membrane glutamate transporters and the increased expression of the vesicular transporter in the hippocampus would affect the balance of the glutamatergic circuitry of the hippocampus, and that this effect may be a major contributor to depressive symptoms.

Abstract

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.

Abstract

Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.

Abstract

Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.

Abstract

Approximately 50% of mood disorder patients exhibit hypercortisolism. Cortisol normally exerts its functions in the CNS via binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Both MR and GR are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR or GR within this region may contribute to the dysregulation in major depressive disorder (MDD). Studies have also shown functional heterogeneity across the hippocampus, with posterior hippocampus preferentially involved in cognitive processes and anterior hippocampus involved in stress, emotion and affect. We therefore hypothesize that GR and MR expression in hippocampus of control and MDD patients may vary not only with disease, but also with regional specificity along the anterior/posterior axis. Student's t-test analysis showed decreased expression of MR in the MDD group compared to controls in the anterior, but not the posterior hippocampus, with no significant changes in GR. Linear regression analysis showed a marked difference in MR:GR correlation between suicide and non-suicide patients in the posterior hippocampus. Our findings are consistent with previous reports of hippocampal corticosteroid receptor dysregulation in mood disorders, but extend those findings by analysis across the anterior/posterior axis of the hippocampus. A decrease in MR in the anterior but not posterior hippocampus of MDD patients emphasizes the important functional role of the anterior hippocampus in neuroendocrine regulation in humans.

Abstract

Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed.There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009).Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

Abstract

The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, "activated" cAMP signaling activity in BPD and "blunted" cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

Abstract

Neuropsychological functioning, in relation to positive and negative symptoms in psychotic major depression (PMD), has not been as thoroughly studied as it has been in schizophrenia. Thus, the current study investigated the associations between positive and negative symptoms with cognitive functioning, with an emphasis on verbal memory in PMD. Attention, working memory, and the executive functioning domains were analyzed among 49 PMD participants. Positive symptoms did not correlate significantly with any measures of verbal memory but did correlate with one measure of attention, working memory, and executive functioning. Negative symptoms correlated significantly with two California Verbal Learning Test-II (CVLT-II) measures of verbal memory and three measures of executive function. Hierarchical regressions were conducted to determine if negative symptoms could predict verbal memory performance after controlling for depression. Of the two verbal memory measures, negative symptoms significantly explained additional variance for CVLT Recognition, but not for CVLT Trials 1-5 total score. Our results provide some evidence that, consistent with the schizophrenia literature, negative symptoms contributed more to verbal memory deficits in PMD than positive symptoms, regardless of depression severity.

Abstract

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.

Abstract

Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

Abstract

Anxiety and depressive disorders are both associated with abnormalities in the processing and regulation of emotion. However, little is known about the similarities and differences between anxiety and depression at the neural level. The authors examined emotional conflict processing using a salient stimulus associated with observable and interpretable behavioral outcomes and with activation in limbic and prefrontal regions implicated in anxiety and depression.Thirty-two healthy comparison subjects, 18 patients with generalized anxiety disorder only, 14 patients with major depression only, and 25 patients with comorbid generalized anxiety disorder and major depression were studied using functional MRI while they performed an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. The authors used behavioral and neural measures to compare trial-by-trial changes in conflict regulation, a test of implicit regulation of emotional processing.Behavioral data indicated that only patients with generalized anxiety (i.e., the anxiety-only and comorbid groups) failed to implicitly regulate emotional conflict. By contrast, deficits in activation and connectivity of the ventral anterior cingulate and amygdala, areas previously implicated in regulating emotional conflict, were found in all patient groups. Depression-only patients, however, compensated for this deficit by also activating the left and right anterior lateral prefrontal cortices, in which activity was correlated with behavioral evidence of successful implicit regulation, thus mediating the disorder-specificity of the behavioral phenotype.These data support the existence of a common abnormality in anxiety and depression in the ventral cingulate and the amygdala, which may be related to a shared genetic etiology. Compensatory engagement of cognitive control circuitry in depression illustrates how the complex nature of psychopathology arises from the interaction of deficits and compensation, all of which can occur at an implicit level.

Abstract

A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study.

Abstract

Several studies have proposed that brain glutamate signaling abnormalities and glial pathology have a role in the etiology of major depressive disorder (MDD). These conclusions were primarily drawn from post-mortem studies in which forebrain brain regions were examined. The locus coeruleus (LC) is the primary source of extensive noradrenergic innervation of the forebrain and as such exerts a powerful regulatory role over cognitive and affective functions, which are dysregulated in MDD. Furthermore, altered noradrenergic neurotransmission is associated with depressive symptoms and is thought to have a role in the pathophysiology of MDD. In the present study we used laser-capture microdissection (LCM) to selectively harvest LC tissue from post-mortem brains of MDD patients, patients with bipolar disorder (BPD) and from psychiatrically normal subjects. Using microarray technology we examined global patterns of gene expression. Differential mRNA expression of select candidate genes was then interrogated using quantitative real-time PCR (qPCR) and in situ hybridization (ISH). Our findings reveal multiple signaling pathway alterations in the LC of MDD but not BPD subjects. These include glutamate signaling genes, SLC1A2, SLC1A3 and GLUL, growth factor genes FGFR3 and TrkB, and several genes exclusively expressed in astroglia. Our data extend previous findings of altered glutamate, astroglial and growth factor functions in MDD for the first time to the brainstem. These findings indicate that such alterations: (1) are unique to MDD and distinguishable from BPD, and (2) affect multiple brain regions, suggesting a whole-brain dysregulation of such functions.

Abstract

The startle response, a simple defensive response to a sudden stimulus signaling proximal threat, has been well studied in rodents and humans, but has been rarely examined in monkeys. The first goal of the present studies was to develop a minimally immobilizing startle measurement paradigm and validate its usefulness by testing two core features of the startle response (habituation and graded responsivity) in squirrel monkey subjects. Two different types of startle stimuli were used: standard broad-band noise bursts, and species-specific alarm vocalizations ("yaps") which are elicited in response to threat in both wild and captive animals. The second goal of the present studies was to test whether yaps produce enhanced startle responsivity due to their increased biological salience compared to simple, non-biologically relevant noise bursts. The third goal of the present studies was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis response to startle stimuli, as little is known about the stress-activating role of startle stimuli in any species. These experiments determined that the whole-body startle response in relatively unrestrained squirrel monkeys habituates across repeated stimulus presentations and is proportional to stimulus intensity. In addition, differential habituation was observed across biologically salient vs. standard acoustic startle stimuli. Responses to "yaps" were larger initially but attenuated more rapidly over trials. Responses to "yaps" were also larger in the early subepochs of the response window but then achieved a lower level than responses to noise bursts in the later subepochs. Finally, adrenocorticotropic hormone and cortisol concentrations were significantly elevated above baseline after startle stimuli presentation, though monkeys did not exhibit differential HPA axis responses to the two types of startle stimuli. The development of monkey startle methodology may further enhance the utility of this paradigm in translational studies of human stress-related psychiatric disorders.

Abstract

Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.

Abstract

The authors sought to better understand the neural circuitry associated with working memory deficits in psychotic major depression by examining brain function during an N-back task.Study subjects were 16 patients with psychotic major depression, 15 patients with nonpsychotic major depression, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back).Relative to the healthy comparison group, both the psychotic and nonpsychotic major depression groups had significantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed significantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipital cortex. The psychotic major depression group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex.The psychotic major depression group showed aberrant parahippocampal activation at a lower demand level than observed in nonpsychotic major depression. While the nonpsychotic major depression group showed abnormalities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unexpected stimuli. Considering the functional connectivity of this cluster with left dorsolateral prefrontal cortex regions, these findings may reflect neural compensation for sensory gating deficits in psychotic major depression.

Abstract

Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849. URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1

Abstract

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei.

Abstract

In the mid-1950s, Levine and his colleagues reported that brief intermittent exposure to early life stress diminished indications of subsequent emotionality in rats. Here we review ongoing studies of a similar process in squirrel monkeys. Results from these animal models suggest that brief intermittent exposure to stress promotes the development of arousal regulation and resilience. Implications for programs designed to enhance resilience in human development are discussed.

Abstract

Our goal was to examine the empirical literature on the effect of personality traits on the medical outcome of cardiac illness.Pub Med and Psychological Abstracts were searched for the years 1990 to September 2009 using the terms personality, personality traits, personality disorder, health, recovery from illness, cardiac illness and surgical recovery. Articles were then selected that were prospective, had a peer review published measure of personality, a standardized measure of outcome of physical illness and at least one year follow up.Seven articles were identified that met our criteria. All seven had a significant finding that personality traits predicted medical outcomes. Of these seven articles six had similar enough measures of personality to be included in a meta analysis. (All used Type D personality.) Meta analysis found an odds ratio of 3.76 for Type D personality traits predicting poorer medical outcome. This indicated that patients with Type D personality had a 276% increase in the odds of a poor medical outcome compared to patients without Type D personality.These findings indicate that personality traits are a strong predictor of medical outcome of cardiac disease.

Abstract

Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit.We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy.Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure.Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy.These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Abstract

To examine the effectiveness of transdermal selegiline for producing cigarette smoking abstinence.Adult smokers were randomly assigned to receive selegiline transdermal system (STS) or placebo given for 8 weeks. All participants received cognitive behavior therapy (CBT). Follow-ups were conducted at 25 and 52 weeks.Community smoking cessation clinic.243 adult smokers (> or =18 years of age; > or =10 cigarettes/day).Expired-air carbon monoxide confirmed 7-day point prevalence abstinence.STS was not superior to placebo. More women than men were abstinent at 52 week follow-up (28% vs 16%, P < 0.05). Behavioral activation (BAS) moderated treatment response (P = 0.01). The survival rate through week 52 for those with high 'drive' scores on the BAS was 47% if assigned to selegiline and 34% if assigned to placebo. The survival rate for those with low 'drive scores' on the BAS was 35% if assigned to selegiline compared to 53% if assigned to placebo.Transdermal selegiline does not appear generally effective in aiding smoking cessation though there may be a selective effect in those smokers with low 'behavioral activation'.

Abstract

Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.

Abstract

Variation in the ATP-binding cassette, subfamily B, member 1 transporter (ABCB1) (multidrug-resistance gene 1) gene has been investigated as a predictor of response to treatment with a variety of medications such as antiarrhythmics, chemotherapeutic agents, anti-HIV medications, and some psychotropics. The ABCB1 gene product, P-glycoprotein, affects the transport of drugs out of many cell types, including endothelial cells at the blood-brain barrier. We sought to determine if ABCB1 polymorphisms predict response to antidepressant treatment in geriatric patients.We compared the effects of ABCB1 genetic variation on the therapeutic response to paroxetine, a P-glycoprotein substrate, and to mirtazapine, which is not thought to be transported by ABCB1, in a sample of 246 elderly patients with major depression treated in a clinical trial setting. A total of 15 single nucleotide polymorphisms in the ABCB1 gene were assessed in each patient. Two of these ABCB1 single nucleotide polymorphisms were earlier reported to predict treatment response in patients prescribed with P-glycoprotein substrate antidepressants.The two earlier identified ABCB1 markers for antidepressant response predicted time to remission in our paroxetine-treated patients, but not in the mirtazapine-treated patients. These results replicate the published findings of others. If a Bonferroni correction for type I error is made, our results do not reach the criteria for statistical significance. However, the Bonferroni correction may be too conservative given the strong linkage disequilibrium among some of the markers and our aim to replicate the earlier published findings.Our study provides confirmation that certain ABCB1 polymorphisms predict response to substrate medications in geriatric patients.

Abstract

It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

Abstract

This study aims (1) to assess the prevalence of Chronic Painful Physical Condition (CPPC) and major depressive disorder (MDD) in the general population; (2) to evaluate their interaction and co-morbidity with sleep and organic disorders; and (3) to investigate their daily functioning and socio-professional consequences. A random sample of 3243 subjects (18years), representative of California inhabitants, was interviewed by telephone. CPPC duration was at least 6months. Frequency, severity, duration and consequences on daily functioning, consultations, sick leave and treatment were investigated. MDD were assessed using DSM-IV criteria. The point prevalence of CPPC was 49% (95% confidence interval: 47.0-51.0%). Back area pain was the most frequent; 1-month prevalence of MDD was at 6.3% (95% CI: 5.5-7.2%); 66.3% of MDD subjects reported at least one CPPC. In 57.1% of cases, pain appeared before MDD. Pain severity was increased by poor sleep, stress and tiredness in MDD subjects. Being confined to bed, taking sick leave and interference of pain with daily functioning were twice as frequent among MDD subjects with CPPC than in non-MDD subjects with CPPC; obese individuals with CP were 2.6 times as likely to have MDD. Pain is highly linked with depressive disorder. It deteriorates physical, occupational and socio-professional activities. Pain and sleep disturbances are a prime motive of consultation rather than depressed mood, underlining the risk of missing a depression diagnosis.

Abstract

Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder.Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation.Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups.These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.

Abstract

Social phobia may seriously impair the functioning of affected individuals. It is frequently associated with other mental disorders.To estimate the co-occurrence of social phobia with major depressive disorder (MDD) and to analyze their interaction.Subjects were 18,980 individuals, aged 15 years or older, representative of the general population of the United Kingdom, Germany, Italy, Spain and Portugal, who were interviewed by telephone. DSM-IV diagnoses were made with the Sleep-EVAL system.The point prevalence for social phobia was 4.4% (95% confidence interval: 4.1-4.7%) of the sample. It was higher in women (odds ratio: 1.6) and decreased with age. MDDs were found in 19.5% of participants with social phobia. Co-occurrence of another anxiety disorder was high and increased when a MDD was present (65.2%). The odds of developing a major depressive episode 2 years after the appearance of the social phobia was of 5.74.Social phobia is highly prevalent in the general population. It increases the risk of developing a MDD and has a high comorbidity with other mental disorders. Social phobia is often present in the course of depression, more obviously during remission period of MDD. Physicians must explore and treat more systematically this frequent pathology.

Abstract

We evaluated dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in canine brain tumors. Magnetic resonance data sets were collected on seven canine intracranial tumors with a 3 T magnet using a T1-weighted fast spin echo fluid attenuated inversion recovery sequence after an IV bolus injection (0.2 mmol/kg) of Gd-DTPA. The tumors were confirmed histopathologically as adenocarcinoma (n=1), ependymoma (n=1), meningioma (n=3), oligodendroglioma (n=1), and pituitary macroadenoma (n=1) The data were analyzed using a two-compartment pharmacokinetic model for estimation of three enhancement parameters, E(R) (rate of enhancement), Kel (rate of elimination), and Kep (rate constant), and a model-free phenomenologic parameter initial area under the Gd concentration curve (IAUGC) defined over the first 90s postenhancement. Pearson's correlations were calculated between parameters of the two methods. The IAUGC has a relatively strong association with the rate of enhancement E(R), with r ranges from 0.4 to 0.9, but it was weakly associated with Kep and Kel. To determine whether any two tumors differed significantly, the Kohnlmogorov-Smirnov test was used. The results showed that there were statistical differences (P < 0.05) between distributions of the enhancement pattern of each tumor. These kinetic parameters may characterize the perfusion and vascular permeability of the tumors and the IAUGC may reflect blood flow, vascular permeability, and the fraction of interstitial space. The kinetic parameters and the IAUGC derived from DCE-MRI present complementary information and they may be appropriate to noninvasively differentiate canine brain tumors although a larger prospective study is necessary.

Abstract

Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

Abstract

To identify distinct subgroups of treatment responders and nonresponders to aid in the development of tailored smoking-cessation interventions for long-term maintenance using signal detection analysis (SDA).The secondary analyses (n = 301) are based on data obtained in our randomized clinical trial designed to assess the efficacy of extended cognitive behavior therapy for cigarette smoking cessation. Model 1 included only pretreatment factors, demographic characteristics, and treatment assignment. Model 2 included all Model 1 variables, as well as clinical data measured during treatment.SDA was successfully able to identify smokers with varying probabilities of maintaining abstinence from end-of-treatment to 52-week follow-up; however, the inclusion of clinical data obtained over the course of treatment in Model 2 yielded very different partitioning parameters.The findings from this study may enable researchers to target underlying factors that may interact to promote maintenance of long-term smoking behavior change.

Abstract

Treatment-resistant depression may be related to polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) or dysregulation of noradrenergic systems. To examine 5-HTTLPR genotypes and responses to treatment, adult patients (N=261) with current major depression and a symptom severity rating > or =8 on the 17-item Hamilton Depression Rating Scale (HAMD(17)) were treated for 8 weeks with open-label sertraline (100-200 mg/d). Patients remaining symptomatic (total score >4, or >1 on any item of the HAMD(17) Maier-Philipp subscale) were randomly assigned to double-blind therapy with sertraline plus either atomoxetine (40-120 mg/d) or placebo for 8 additional weeks. 5-HTTLPR genotype did not predict responses to sertraline monotherapy or discontinuation rates. Among the 138 patients remaining symptomatic after sertraline monotherapy (L/L = 21%, S/L = 50%, S/S = 29%), significantly more S/S-genotype patients achieved remission under combined sertraline/atomoxetine treatment relative to the other genotypes (S/S = 81.8%; non-S/S = 32.7%), but not under sertraline/placebo treatment (S/S = 35.7%; non-S/S = 37.7%). Minor genotypic differences were noted in adverse event profiles. In patients with poor responses to sertraline monotherapy for depression, addition of atomoxetine may improve responses to treatment of depression in S/S-genotyped patients. Although this study is speculative, it represents a pharmacologically and genotypically well-defined patient population.

Abstract

A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.

Abstract

Identifying factors that influence mental health outcomes in veterans can aid in the redesign of programs to maximize the likelihood of early resolution of problems. To that end, we examined demographic and clinical process data from 2,684 veterans who scored positive on a mental health screen. We investigated this data set for patterns and possible predictors of mental health referral acceptance and attendance. The majority of patients had not received mental health treatment within the last two years (76%). Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) were more likely to accept a mental health referral for depression but were equally likely to attend a mental health visit as other era veterans. Decreased acceptance was associated with provider type and contact method, clinic location, depression only, and specific age ranges (65-74). Among those who accepted a referral, decreased attendance was associated with clinic location, depression only, and retirement. No variables predicted OEF/OIF acceptance/attendance. In conclusion, our findings illustrate the importance of close, continual monitoring of clinical process data to help reveal targets for improving mental health care for veterans.

A pilot study of the phase angle between cortisol and melatonin in major depression - A potential biomarker?JOURNAL OF PSYCHIATRIC RESEARCHBuckley, T. M., Schatzberg, A. F.2010; 44 (2): 69-74

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis and melatonin rhythm alterations have been independently reported in major depression (MDD) as well as in insomnia. In this pilot study, we link cortisol and melatonin rhythms and propose that the phase angle between cortisol acrophase (CA) and dim-light melatonin onset (20 pg/ml) (DLMO-20) may yield a useful state specific biomarker for MDD.Six healthy (HC) and six depressed (MDD) psychotropic free subjects were admitted to the General Clinical Research Center. Blood was sampled for cortisol and melatonin from 1600h to 1000h, under dim lights (<20lux) and constant routine. Time for DLMO-20 and peak cortisol concentration was determined for each subject. Phase angle was computed as the difference in time between CA and DLMO-20.Phase angle was significantly increased in MDD's versus HC's (13.40+/-1.61h. versus 11.61+/-1.66h, p=0.026). Using ROC analysis, a phase angle greater than 13.57h distinguished MDD's from HC's (sensitivity=0.83, specificity=1.0). Mean nocturnal melatonin (1600-1000h) was significantly decreased in MDD's versus HC's (22.67+/-9.08 pg/ml versus 47.82+/-14.76 pg/ml, p=0.015).The phase angle between CA and DLMO-20 appears to distinguish HC's from MDD's and may be a useful biomarker to aid biologic assessment as well as treatment. Lower nocturnal melatonin in MDD's highlights its importance in MDD's pathophysiology. Additional study with larger sample size is needed to confirm the results of this pilot study. The mechanism for this phase angle difference and decreased melatonin, itself, requires further study.

Abstract

Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD.To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD.Cross-sectional study.Academic medical center.Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry.Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network.Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

Abstract

Nicotine dependence may be expressed differently in teens than in adults. Thus, it may not be sufficient to build diagnostic and cessation treatment strategies for teens based on adult-derived clinical and research data. This is the first study to prospectively examine the development of withdrawal symptoms by level of nicotine dependence among adolescent smokers. Forty-seven adolescent smokers completed nicotine withdrawal symptoms measures during 10 weeks of cessation treatment. Nicotine dependence was assessed at baseline using the mFTQ. Change in withdrawal symptoms over time by level of nicotine dependence was examined via mixed model ANOVA. Nicotine withdrawal in daily adolescent smokers was strongly and prospectively associated with the level of nicotine dependence. Craving was rated as the most problematic symptom at the baseline assessment. The results of this study may help guide the development of future research on diagnostic and cessation treatment strategies for teens.

Abstract

The purpose of this study was to examine the effects of glucose reduction stress on lymphoblastic cell line (LCL) gene expression in subjects with schizophrenia compared to non-psychotic relatives.LCLs were grown under two glucose conditions to measure the effects of glucose reduction stress on exon expression in subjects with schizophrenia compared to unaffected family member controls. A second aim of this project was to identify cis-regulated transcripts associated with diagnosis.There were a total of 122 transcripts with significant diagnosis by probeset interaction effects and 328 transcripts with glucose deprivation by probeset interaction probeset effects after corrections for multiple comparisons. There were 8 transcripts with expression significantly affected by the interaction between diagnosis and glucose deprivation and probeset after correction for multiple comparisons. The overall validation rate by qPCR of 13 diagnosis effect genes identified through microarray was 62%, and all genes tested by qPCR showed concordant up- or down-regulation by qPCR and microarray. We assessed brain gene expression of five genes found to be altered by diagnosis and glucose deprivation in LCLs and found a significant decrease in expression of one gene, glutaminase, in the dorsolateral prefrontal cortex (DLPFC). One SNP with previously identified regulation by a 3' UTR SNP was found to influence IRF5 expression in both brain and lymphocytes. The relationship between the 3' UTR rs10954213 genotype and IRF5 expression was significant in LCLs (p = 0.0001), DLPFC (p = 0.007), and anterior cingulate cortex (p = 0.002).Experimental manipulation of cells lines from subjects with schizophrenia may be a useful approach to explore stress related gene expression alterations in schizophrenia and to identify SNP variants associated with gene expression.

Abstract

The Research Career Development Institute for Psychiatry is a collaboration between the University of Pittsburgh and Stanford University to recruit and train a broad-based group of promising junior physicians by providing the necessary skills and support for successful research careers in academic psychiatry.Participants whose interests span the spectrum of clinical and intervention research attend a multiday career development institute workshop and follow-up annual booster sessions conducted with the American College of Neuropsychopharmacology. The program identifies and trains 20 new physician-researchers each year, with particular emphasis on women, minorities, and those from less research-intensive psychiatry departments, and provides booster sessions for all trainees. An annual evaluation is used to renew and update the content of the institutes and to measure the long-term value in research and career success.This report is based on the results of 77 participants from the first four Career Development Institute classes. Qualitative assessment of the program content and process led to improvements in each successive year's workshop. Preliminary quantitative follow-up assessment of participants indicated successful career progress toward individual objectives.By providing early career investigators with skills to cope with local and national forces in academic medical centers, the Career Development Institute is significantly contributing to the development of the next generation of leading academic clinical researchers in mental health and can serve as a model for other biomedical research arenas.

Abstract

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

Abstract

Psychiatry includes the assessment, treatment, and prevention of complex brain disorders, such as depression, bipolar disorder, anxiety disorders, schizophrenia, developmental disorders (e.g., autism), and neurodegenerative disorders (e.g., Alzheimer dementia). Its core mission is to prevent and alleviate the distress and impairment caused by these disorders, which account for a substantial part of the global burden of illness-related disability. Psychiatry is grounded in clinical neuroscience. Its core mission, now and in the future, is best served within this context because advances in assessment, treatment, and prevention of brain disorders are likely to originate from studies of etiology and pathophysiology based in clinical and translational neuroscience. To ensure its broad public health relevance in the future, psychiatry must also bridge science and service, ensuring that those who need the benefits of its science are also its beneficiaries. To do so effectively, psychiatry as clinical neuroscience must strengthen its partnerships with the disciplines of public health (including epidemiology), community and behavioral health science, and health economics.The authors present a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis of psychiatry and identify strategies for strengthening its future and increasing its relevance to public health and the rest of medicine. These strategies encompass new approaches to strengthening the relationship between psychiatry and neurology, financing psychiatry's mission, emphasizing early and sustained multidisciplinary training (research and clinical), bolstering the academic infrastructure, and reorganizing and refinancing mental health services both for preventive intervention and cost-effective chronic disease management.

Abstract

Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.Dorsolateral prefrontal cortex (DLPFC) from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C) was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017) in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK) was significant (p = 0.004) and independent of postmortem interval time.Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.

Abstract

Coping with mild early life stress tends to make subsequent coping efforts more effective and therefore more likely to be used as a means of arousal regulation and resilience. Here we show that this developmental learning-like process of stress inoculation increases ventromedial prefrontal cortical volumes in peripubertal monkeys. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that the process of coping with early life stress increases prefrontal myelination and expands a region of cortex that broadly controls arousal regulation and resilience.

Abstract

The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy.276 patients with major depressive disorder (MDD) were treated with sertraline (150-200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy.The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy.This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials.

Abstract

Stressful experiences that are challenging but not overwhelming appear to promote the development of arousal regulation and resilience. Variously described in studies of humans as inoculating, steeling, or toughening, the notion that coping with early life stress enhances arousal regulation and resilience is further supported by longitudinal studies of squirrel monkey development. Exposure to early life stress inoculation diminishes subsequent indications of anxiety, increases exploration of novel situations, and decreases stress-levels of cortisol compared to age-matched monkeys raised in undisturbed social groups. Stress inoculation also enhances prefrontal-dependent cognitive control of behavior and increases ventromedial prefrontal cortical volumes. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that early life stress inoculation triggers developmental cascades across multiple domains of adaptive functioning. Prefrontal myelination and cortical expansion induced by the process of coping with stress support broad and enduring trait-like transformations in cognitive, motivational, and emotional aspects of behavior. Implications for programs designed to promote resilience in humans are discussed.

Abstract

PRIMARY AIM: Examine the effectiveness of extended cognitive behavior therapy (CBT) in promoting longer-term smoking abstinence.Open-label treatment phase followed by extended treatment phase. Randomization conducted prior to entry into open-label treatment phase; analysis based on intention-to-treat to avoid threat of selection bias.Community smoking cessation clinic.A total of 304 adult smokers (> or = 18 years of age; > or = 10 cigarettes/day).Open-label (8 weeks): all participants received bupropion SR, nicotine patch, CBT. Extended treatment (12 weeks): participants received either CBT + voicemail monitoring and telephone counseling or telephone-based general support.Seven-day point prevalence abstinence, expired-air carbon monoxide.At week 20 follow-up, CBT produced a higher 7-day point prevalence abstinence rate: 45% versus 29%, P = 0.006; at 52 weeks the difference in abstinence rates (31% versus 27%) was not significant. History of depression was a moderator of treatment. Those with a positive history had a better treatment response at 20 weeks when assigned to the less intensive telephone support therapy (P < 0.05).The superiority of CBT to 20 weeks suggests that continued emphasis on the development of cognitive and behavioral strategies for maintaining non-smoking during an extended treatment phase may help smokers to maintain abstinence in the longer term. At present, the minimum duration of therapy is unknown.

Abstract

The limbic system is thought to underlie dysfunctional affective and cognitive processes in individuals with depression. Neuroanatomical studies of subjects with depression have often examined hippocampal and amygdalar structures, since they are two key structures of the limbic system. Research has often but not always found reduced hippocampal volume in patients with major depression. The purpose of the present study was to examine differences in hippocampal and amygdalar volumes in patients with depression subtypes relative to healthy comparison subjects.Participants were 1) patients with major depression with psychosis, 2) patients with major depression without psychosis, and 3) healthy comparison subjects. To examine hippocampal and amygdalar volumes, all participants underwent structural magnetic resonance imaging (MRI). The authors further examined the effects of clinical and chronicity data on these two brain structures.After age, gender, and total brain volume were controlled, depressed patients with psychosis had a significantly smaller mean amygdala volume relative to depressed patients without psychosis and healthy comparison subjects. There were no differences between depressed patients without psychosis and healthy comparison subjects. Correlational analyses suggested that age of depression onset was strongly associated with amygdala volume. No group differences in hippocampal volume were found.There were no differences between depressed patients and healthy comparison subjects in hippocampal volume. However, psychotic but not nonpsychotic depression was associated with reduced amygdala volume. Reduced amygdala volume was not associated with severity of depression or severity of psychosis but was associated with age at onset of depression. Smaller amygdala volume may be a risk factor for later development of psychotic depression. In addition, chronicity of depression and depression subtype might be two important factors associated with hippocampal and amygdalar volumes in depression.

Abstract

Neuropsychiatric disorders often involve considerable psychological stress and elevated cortisol activity. Glucocorticoid receptors have relatively low affinity for cortisol and are found distributed throughout the brain, particularly in the frontal cortex and hippocampus. In recent years, glucocorticoid receptors antagonists have been actively studied in both animal models of several disorders as well as a potential treatment in specific types of neuropsychiatric patients. Data from these various studies are reviewed with an emphasis on seven clinical disorders or problems: major depression with psychotic features, bipolar disorder, schizophrenia, cognitive disorders, (e.g., Alzheimer's disease and mild cognitive impairment), cognitive side effects of electroconvulsive therapy, and weight gain with atypical antipsychotic agents. Potential benefits and limitations are discussed.

Abstract

This report presents the rationale, design, and baseline sample characteristics for the REVAMP study. This project is a multisite clinical trial designed to evaluate the efficacy of augmenting state-of-the-art pharmacotherapy with psychotherapy in chronically depressed patients who fail to respond or respond incompletely to an initial trial of antidepressant medication.Chronic forms of major depression disorder (cMDD) are longitudinally continuous forms of major depressive disorder (MDD), and may account for a significant portion of the societal burden of disease associated with M D D. Antidepressant medications and depression-focused psychotherapies have been shown to be effective for cMDD, though the majority fail to achieve remission following an acute course of treatment. There is a pressing need to evaluate whether the outcomes obtained from a well implemented medication algorithm combined with depression-focused psychotherapy can significantly enhance outcomes for cMDD.Although there is evidence for the effectiveness of depression-focused psychotherapy for the treatment of cMDD, this is the first prospective, randomized, controlled trial investigating psychotherapy as an augmentation strategy for patients with cMDD incompletely responsive to a trial of antidepressant medication.The REVAMP study has three specific aims: first, to compare the efficacy of adding psychotherapy to a medication change versus changing medication alone in chronic depressives with partial response or nonresponse to an initial trial of antidepressant medication; second, to test efficacy of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) as an augmentation strategy by comparing it to Supportive Psychotherapy (SP); and third, to test a hypothesized mechanism of therapeutic action of CBASP by examining whether patients receiving CBASP exhibit significantly greater improvements in social problem solving than patients receiving adjunctive SP or continued medication alone. As a subsidiary aim, the study also compares the effects of the three randomized treatments on psychosocial outcomes.The study involves two 12-week phases. During Phase 1, patients with cMDD receive antidepressant monotherapy selected according to an algorithm that takes into account their prior treatment history. Their pattern of response is evaluated, those with no response at 8 weeks or less than a full response at 12 weeks advance to Phase 2. At the beginning of Phase 2, patients who did not respond to the initial antidepressant monotherapy during Phase 1 are switched to the next medication in the pharmacotherapy algorithm and randomly assigned in a 2:2:1 ratio to one of three treatment cells: 16 sessions of either CBASP (40% of randomizations) or SP (40%) added to pharmacotherapy, or medication alone (20%) with no added psychotherapy. Similarly, patients achieving a partial response during Phase 1 have their initial medication augmented with a second antidepressant agent during Phase 2 and are randomly assigned to either CBASP, SP, or medication alone. Patients who achieve remission during Phase 1 are not randomized to Phase 2, but rather are monitored monthly for an additional 12 weeks.Recent sequential treatment studies have provided state-of-the-art knowledge about the need for multiple steps in order to achieve remission. The current study, therefore, provides an important next step in understanding the role of depression-focused psychotherapy in a treatment algorithm so essential in the management of difficult-to-treat depression such as chronic forms of major depression.

Abstract

Recent findings of mitochondrial abnormalities in brains from subjects with neurological disorders have led to a renewed search for mitochondrial abnormalities in psychiatric disorders. A growing body of evidence suggests that there is mitochondrial dysfunction in schizophrenia, bipolar disorder, and major depressive disorder, including evidence from electron microscopy, imaging, gene expression, genotyping, and sequencing studies. Specific evidence of dysfunction such as increased common deletion and decreased gene expression in mitochondria in psychiatric illnesses suggests that direct examination of mitochondrial DNA from postmortem brain cells may provide further details of mitochondrial alterations in psychiatric disorders.

Abstract

We evaluated the comparative efficacy and safety of venlafaxine extended release (ER) and fluoxetine in the acute and continuation phases of treatment.In this multicenter, double-blind study, outpatients with recurrent unipolar major depression were randomly assigned to receive venlafaxine ER (75-300 mg/day; n = 821) or fluoxetine (20-60 mg/day; n = 275). After a 10-week acute treatment phase, responders entered a 6-month continuation phase of ongoing therapy with double-blind venlafaxine ER (n = 530) or fluoxetine (n = 185). In the acute phase, the primary outcome was response, defined as a 17-item Hamilton Depression Rating Scale (HDRS) score < or =12 or > or =50% decrease from baseline; the secondary outcome was remission, defined as a HDRS score < or =7. In the continuation phase, the primary outcome was the proportion of patients who sustained response or remission. Secondary measures included time to onset of sustained response or remission (i.e., meeting criteria at two or more consecutive visits), relapse rates, and quality-of-life measures.At the acute treatment phase end point, response rates were 79% for both venlafaxine ER and fluoxetine; remission rates were 49% and 50% for venlafaxine ER and fluoxetine, respectively. In the continuation phase, response rates were 90% and 92%, and remission rates were 72% and 69% for venlafaxine ER and fluoxetine, respectively. Rates of sustained remission at the end of the continuation phase were 52% and 58% for venlafaxine ER and fluoxetine, respectively.Venlafaxine ER and fluoxetine were comparably effective during both acute and continuation phase therapy.

Abstract

Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.

Abstract

Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.

Abstract

Both glucocorticoid and mineralocorticoid receptors (GRs and MRs) help modulate cortisol feedback on the hypothalamic-adrenal-pituitary (HPA) axis. In brain, MRs inhibit the HPA axis and are thought to be fully occupied. Thus, prior studies of the effects of an MR agonist on HPA axis activity have first used metyrapone to inhibit cortisol production and to consequently deplete the receptors. Herein, we propose that an MR agonist may inhibit the HPA axis without first "unloading" receptors of endogenous cortisol.Healthy subjects were admitted to the General Clinical Research Center. Blood was sampled for cortisol and adrenocorticotropic hormone (ACTH) from 16:00 to 24:00 h, when greatest MR activity is expected, on two consecutive nights. The first night established a baseline and the second night established response. On the second afternoon, all subjects were given 0.5mg fludrocortisone. Mean cortisol and ACTH were computed from 16:00 to 24:00 h.Fludrocortisone acutely decreased mean cortisol (p=0.003; effect size (ES) 1.65) and mean ACTH (p=0.000, ES 4.46). Additionally, post hoc analysis showed that fludrocortisone tended to decrease the cortisol/ACTH ratio (p=0.0686, ES 0.92) across the same time period.Fludrocortisone significantly inhibits nocturnal HPA axis activity without first depleting MR receptors with metyrapone. This suggests that brain MRs are not fully occupied by endogenous cortisol and can be further activated by an agonist. The decrease in cortisol/ACTH ratio suggests a possible role on adrenal sensitivity as well. The ability to lower nocturnal HPA axis activity has interesting implications in disorders of HPA axis excess, such as insomnia, depression and healthy aging.

Abstract

Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls.Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity.Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate.This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

Abstract

Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.

Abstract

To report second-year results from the 2-year maintenance phase of a long-term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression.Outpatients with recurrent unipolar depression (DSM-IV criteria; N = 1096) were randomly assigned in a 3:1 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. Responders (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score or= 50% decrease from baseline) entered a 6-month, double-blind continuation phase on the same medication. Continuation-phase responders were enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo, and fluoxetine responders were continued for each period. The second 12-month maintenance phase compared the time to recurrence of depression with venlafaxine ER (75 to 300 mg/day) versus placebo as the primary efficacy measure. The primary definition of recurrence was a HAM-D(17) total score > 12 and < 50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. The time to recurrence was evaluated using Kaplan-Meier methods and compared between the venlafaxine ER and placebo groups using log-rank tests. Secondary outcome measures included rates of response and remission (defined as HAM-D(17) = 7). The study was conducted from December 2000 through July 2005.The cumulative probabilities of recurrence through 12 months in the venlafaxine ER (N = 43) and placebo (N = 40) groups were 8.0% (95% CI = 0.0 to 16.8) and 44.8% (95% CI = 27.6 to 62.0), respectively (p < .001). At month 12, using last-observation-carried-forward analysis, the rate of response or remission was significantly higher in the venlafaxine ER group (93%) than in the placebo group (63%; p = .002). Overall discontinuation rates were 28% and 63% in the venlafaxine ER and placebo groups, respectively. Adverse events were the primary reason for discontinuation for 1 patient (2%) in the venlafax-ine ER group and 4 (10%) in the placebo group. An analysis of the combined maintenance phases, which compared the risk of recurrence over 24 months for patients assigned to venlafaxine ER (N = 129) or placebo (N = 129) for the first maintenance phase, showed a significantly greater cumulative probability of recurrence through 24 months for the placebo group (47.3% [95% CI = 36.4 to 58.2]) than for the venlafaxine ER group (28.5% [95% CI = 18.3 to 38.7]; p = .005).In this study, an additional 12 months of maintenance therapy with venlafaxine ER was effective in preventing recurrence of depression in patients who had been responders to venlafaxine ER after acute (10 weeks), continuation (6 months), and initial maintenance (12 months) therapy.ClinicalTrials.gov identifier NCT00046020 (http://www.clinicaltrials.gov).

Abstract

Depression is one of the most common mental disorders worldwide. There are a number of depression subtypes, and there has been much debate about how to most accurately capture and organize the features and subtypes of major depression. We review the current state of categorizing unipolar major depression with psychotic features (psychotic major depression, PMD), including clinical, biological, and treatment aspects of the disorder. We then propose some improvements to the current unipolar major depression categorization system. Finally, we identify important issues in need of further research to help elucidate the subtype of unipolar PMD.

Abstract

To test the long-term efficacy and safety of venlafaxine extended-release (ER) in preventing recurrence in patients with major depression.This multiple-phase study, entitled "Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years" (PREVENT), was conducted from December 2000 through July 2005 in patients with recurrent unipolar depression (DSM-IV) who were initially randomly assigned to double-blind treatment with venlafaxine ER (75 mg/day to 300 mg/day) or fluoxetine (20 mg/day to 60 mg/day) for 10 weeks of acute treatment. Responders then received 6 months of continuation treatment. Those who remained responders were then enrolled into a 12-month maintenance period. Venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo. Fluoxetine responders were not randomly assigned but continued taking fluoxetine in order to maintain the blind during the maintenance study. Time to recurrence of depression (17-item Hamilton Rating Scale for Depression total score > 12 and < 50% reduction from acute phase baseline) with venlafaxine ER versus that of placebo were compared.The efficacy evaluable sample consisted of 129 patients in each group. The mean daily dose of venlafaxine ER was 224.7 mg (SD = 66.7). The cumulative probability of recurrence through 12 months, based on the primary definition, was 23.1% (95% CI = 15.3 to 30.9) for venlafaxine ER and 42.0% (95% CI = 31.8 to 52.2) for placebo (p = .005, log-rank test).Patients who had been successfully treated with venlafaxine ER during acute and continuation therapy were significantly less likely to experience recurrence with venlafaxine ER than with placebo over a 12-month maintenance treatment period.ClinicalTrials.gov identifier NCT00046020.

Abstract

The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

Abstract

IMS Health Inc data presented by the Food and Drug Administration (FDA) on September 13 and 14, 2004, at a joint meeting of the Center for Drug Evaluation and Research's Psychopharmacologic Drugs Advisory Committee and the FDA's Pediatric Advisory Committee suggested that the number of children and teenagers who were prescribed antidepressants continued to increase in 2004, despite widespread publicity surrounding 2 FDA advisories regarding the potential for pediatric suicidality with selective serotonin reuptake inhibitor use. These results are contradictory to findings from the Medco Health Solutions, Inc, March 2004 analysis of pharmacy benefit claims and a separate subsequent analysis conducted by NDC Health using dispensing data from March 31, 2004, through June 30, 2005.To investigate the contradictory findings and provide additional analyses on the prescribing trends of antidepressants across age groups and physician specialties in the United States.Retail pharmacy prescription data and physician audit data were obtained from Verispan, a joint venture between Quintiles Transnational and McKesson. In addition to examining prescribing trends, a joinpoint regression analysis was conducted to identify the timing for significant changes in prescription use.The analyses suggest that the number of children and teenagers who were prescribed antidepressants has decreased significantly (P = .02) in the wake of widespread publicity surrounding the FDA public health advisories. Another impact of the advisories seems to be a shift in care from "generalists" to psychiatric specialists when it comes to prescribing antidepressants to patients younger than 18 years. Finally, the analyses highlight a slight shift in prescribing toward the non-selective serotonin reuptake inhibitor bupropion hydrochloride, even though it carries the same FDA "black box" warning as the selective serotonin reuptake inhibitors.The effect on antidepressant prescribing volume observed in our analysis of the Verispan data parallels earlier findings reported by Medco Health Solutions, Inc, and NDC Health that the FDA actions have had a significant effect on the prescribing of antidepressants to children and adolescents. Together, these findings underline the importance of presenting a fair balance within the media due to the significant reach of this channel among prescribing physicians.

Abstract

Despite appropriate treatment with selective serotonin reuptake inhibitors (SSRIs), many depressed patients do not attain remission. Addition of a noradrenergic intervention in patients poorly or partially responsive to SSRIs may improve outcomes, but few well-controlled studies testing this hypothesis have been reported.Patients with major depressive disorder (confirmed by the Structured Clinical Interview for DSM-IV) were treated with sertraline at doses up to 200 mg/day in this study, conducted from June 18, 2003, to January 28, 2005. Patients who continued to experience depressive signs and symptoms after 8 weeks were randomly assigned to have atomoxetine 40 to 120 mg/day or placebo added to sertraline for a further 8 weeks.Of 276 patients starting the study, 146 with persistent depressive symptoms after 8 weeks of sertraline treatment (mean [SD] final sertraline dose: 161.1 [43.4] mg/day) were randomly assigned to addition of atomoxetine or placebo. After 8 additional weeks, there was no difference between treatment groups in mean change in symptom severity or in the proportion of patients whose symptoms remitted (sertraline/ atomoxetine 29/72 [40.3%], sertraline/placebo 28/74 [37.8%], p = .865). Secondary analyses that separated the subgroups with improvements in symptoms that did not reach remission (partial responders) and those with little or no improvement (nonresponders) also showed no effect of atomoxetine. The number of patients discontinuing because of adverse events did not differ between groups.In depressed patients with persistent symptoms after an initial trial of sertraline, addition of atomoxetine did not improve response more than placebo.

Abstract

Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

Abstract

Optimal management of depression remains a long-term challenge. Long-term maintenance treatment with antidepressants has been shown to be effective for preventing or delaying recurrence for many patients with a history of previous multiple episodes. However, aside from a history of multiple recurrences, it remains difficult to identify patients who are most likely to experience recurrence and when. Thus we do not really know who might particularly benefit from maintenance therapy and what type may be efficacious. In patients with depression, research has shown there are structural and functional alterations in the brain, particularly in patients with recurrent or chronic depression. These changes have been generally viewed to be consequences of the disease, which are seen to worsen with a longer duration of untreated illness and with a greater number of depressive episodes. However, these neurobiological characteristics may also represent risk factors or vulnerabilities that predispose some patients to chronic or recurrent depression. Additional research has demonstrated that antidepressant treatment may reduce or modulate these functional and structural changes, suggesting that long-term treatment may, in fact, benefit patients not only by controlling symptoms but also by managing these underlying vulnerabilities. A new treatment paradigm, which focuses on identifying patients with risk factors and managing the disease process rather than suppression of symptoms, is needed for recurrent depression.

Abstract

Although social stress inhibits neurogenesis in the adult hippocampus, the extent to which individual differences in stress-related behavior affect hippocampal cell proliferation is not well understood. Based on results from resident-intruder stress tests administered to adult male mice, here we report that individual differences in hippocampal cell proliferation are related to the frequency of defensive behavior, and not the amount of aggression received or the frequency of fleeing. In contrast, access to voluntary wheel-running exercise did not affect hippocampal cell proliferation in either stressed or non-stressed mice. Social stress-induced inhibition of cell proliferation was restricted to the hippocampus, as neither stress nor access to wheel-running exercise altered cell proliferation in the amygdala. These findings indicate that individual differences in stress-related behavior influence cell proliferation in the mouse hippocampus, and may have important implications for understanding structural and functional hippocampal impairments in human psychiatric patients.

Abstract

Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits.Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained.PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory.While PMDs' ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory.

Abstract

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.

Abstract

Increased hypothalamic-pituitary-adrenal axis activity is well described in psychotic depression with an emphasis on 24-hour, urinary free cortisol levels or dexamethasone suppression tests. There are limited data on cortisol levels during specific times of the day.Patients with depression with (PMD) and without (NPMD) psychosis and healthy control subjects were studied using rating scales of depression and psychosis and measures of HPA activity, including overnight cortisol and adrenocorticotropin levels. We used analysis of variance to determine group differences and regression analyses to assess contributions of specific measures to cortisol levels.PMDs had higher cortisol during the evening hours than did NPMDs or control subjects, who did not differ from one another. Regression analyses suggest that depression and the combination of depressive and psychotic symptoms were important contributors to variance in evening cortisol.PMD is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing's syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.

Abstract

Despite the high prevalence of depression in elderly patients, few well-designed, placebo-controlled studies of antidepressants have been conducted in this population. This masked, placebo-controlled trial assessed the efficacy and safety of venlafaxine and fluoxetine in depressed patients older than 65 years.Three hundred patients were randomly assigned to treatment with venlafaxine immediate release ([IR]; N = 104), fluoxetine (N = 100), or placebo (N = 96) in an eight-week trial. Venlafaxine doses were titrated from 37.5 to 225 mg per day and fluoxetine doses were titrated from 20 to 60 mg per day, as necessary, over 29 days. Efficacy variables included the 21-item Hamilton Depression Rating Scale (HAM-D21) total score, HAM-D21 depressed mood item score, scores on the Montgomery Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity of Illness (CGI-S) and Improvement (CGI-I) scales, and rates of response (based on change from baseline HAM-D or MADRS score or CGI-I score) and remission (HAM-D17 < or =7). For the purposes of this report, efficacy analyses are focused on the HAM-D21 total score. Safety assessments included monitoring of adverse events (AEs), physical examinations, vital signs assessments, laboratory determinations, and electrocardiograms.In all three of the treatment groups, there was a significant reduction at week 8 compared with the baseline HAM-D21 total score. However, there were no significant differences among the three treatment groups on the change in HAM-D21, MADRS, or CGI scores from baseline to week 8. There was no statistically significant difference in the proportion of remitters at the last on-therapy visit. The incidence of individual AEs was higher in the venlafaxine group (27%) compared with patients taking fluoxetine (19%) or placebo (9%).In this study, there was no significant difference in efficacy among placebo, venlafaxine, and fluoxetine for the treatment of depression.

Abstract

Gene expression profiling of brain tissue samples applied to DNA microarrays promises to provide novel insights into the neurobiological bases of primate behavior. The strength of the microarray technology lies in the ability to simultaneously measure the expression levels of all genes in defined brain regions that are known to mediate behavior. The application of microarrays presents, however, various limitations and challenges for primate neuroscience research. Low RNA abundance, modest changes in gene expression, heterogeneous distribution of mRNA among cell subpopulations, and individual differences in behavior all mandate great care in the collection, processing, and analysis of brain tissue. A unique problem for nonhuman primate research is the limited availability of species-specific arrays. Arrays designed for humans are often used, but expression level differences are inevitably confounded by gene sequence differences in all cross-species array applications. Tools to deal with this problem are currently being developed. Here we review these methodological issues, and provide examples from our experiences using human arrays to examine brain tissue samples from squirrel monkeys. Until species-specific microarrays become more widely available, great caution must be taken in the assessment and interpretation of microarray data from nonhuman primates. Nevertheless, the application of human microarrays in nonhuman primate neuroscience research recovers useful information from thousands of genes, and represents an important new strategy for understanding the molecular complexity of behavior and mental health.

Abstract

Psychotic major depression (PMD) is found to be a relatively common psychiatric condition that affects up to nearly 20% of patients with major depression. Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone, in addition to restoring a more normal afternoon cortisol release. The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed. In total, 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a randomized double-blind manner. The Hamilton Depression Rating Scale (HDRS) and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment. Significantly, more patients in the mifepristone group (seven of 15) showed a 50% or greater decline on the BPRS positive symptom subscale, an index of psychotic symptoms, as compared to the placebo group (two of 15). Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo, but these differences were not statistically significant. In addition, mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo. Clinical and biological effects of mifepristone were comparable among males and females. Age was found to significantly and positively correlate with changes in cortisol and ACTH. These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may re-regulate the HPA axis. Additional blinded studies are warranted.

Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primatesPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAParker, K. J., Buckmaster, C. L., Sundlass, K., Schatzberg, A. F., Lyons, D. M.2006; 103 (8): 3000-3005

Abstract

The stress inoculation hypothesis presupposes that brief intermittent stress exposure early in life induces the development of subsequent stress resistance in human and nonhuman primates. Rodent studies, however, suggest a role for maternal care rather than stress exposure per se (i.e., the maternal mediation hypothesis). To investigate these two hypotheses, we examined maternal care and the development of stress resistance after exposure to brief intermittent infant stress (IS), mother-infant stress (MIS), or no stress (NS) protocols administered to 30 monkeys between postnatal weeks 17 and 27. Unlike rodents, the IS condition did not permanently increase primate maternal care, nor did measures of total maternal care predict subsequent offspring hypothalamic-pituitary-adrenal-axis responsivity. Although MIS infants received less maternal care than IS and NS infants, both IS and MIS monkeys developed subsequent stress resistance. These findings indicate that rearing differences in the development of stress resistance are more closely related to differences in prior stress exposure than to differences in maternal care. A second experiment confirmed this conclusion in a different cohort of 25 monkeys exposed as infants to high foraging-demand (HFD) or low foraging-demand (LFD) conditions. HFD infants exhibited intermittent elevations in cortisol levels and received less maternal care than LFD infants. In keeping with a key prediction of the stress inoculation hypothesis, HFD males responded to stress in adulthood with diminished hypothalamic-pituitary-adrenal-axis activation compared with LFD males. Results from both experiments demonstrate that stress inoculation, rather than high levels of maternal care, promotes the development of primate stress resistance.

Abstract

The aim of this study was to assess whether individual or clusters of psychiatric symptoms can differentiate patients with psychotic major depression (PMD) from those with nonpsychotic depression (NPMD).Data were pooled from two studies investigating patients with moderate depression. A total of 129 subjects were studied. Patients in Sample 1 were unmedicated, while the majority of the patients in Sample 2 were taking psychotropic medications. Baseline rating scales were obtained for all subjects, including the Hamilton depression rating scale and the brief psychiatric rating scale (BPRS). We used discriminant function analyses, logistic regression, and ROC analyses to determine the patterns in symptoms that differentiated the groups.Psychotic patients were adequately differentiated by the unusual thought content (UTC) item of the BPRS. Even mild UTC endorsement was an indicator of PMD. Furthermore, results suggest that the positive symptom subscale of the BPRS was even better at differentiating PMD from NMPD patients. Sensitivity and specificity for this scale were 84% and 99%, respectively.Psychotic major depression is often undiagnosed and poorly treated. One reason for this trend is the failure of physicians to inquire in a more detailed manner about positive symptoms in patients with primary mood symptoms. Although physicians are not likely to have the time to conduct an entire BPRS during an evaluation, our results suggest that a few key symptoms, if assessed directly, may aid the psychiatrist to more effectively diagnose and subsequently treat their depressed patients.

Abstract

Currently, no evidence-based guidelines exist for the management of serotonin reuptake inhibitor (SRI) discontinuation syndrome. This article summarizes recommendations with respect to future research as well as clinical management recommendations for SRI discontinuation syndrome.In April 2004, a panel of physicians convened in New York City to discuss recommendations for clinical management of and additional research on SRI discontinuation syndrome.Previous guidance for management of SRI discontinuation syndrome was proposed in 1997 in a consensus meeting also chaired by Alan F. Schatzberg. A literature search of the PubMed database was conducted to identify articles on SRI discontinuation syndrome that have been published since 1997.The 2004 panel reviewed important preclinical and clinical studies, discussed prospective investigation of this syndrome in clinical trials, and suggested the establishment of a research network to collect data in naturalistic settings. The panel also reviewed the management recommendations published in 1997 and subsequently updated the recommendations, taking into account the latest clinical data as well as the personal experience of its members with patients.Additional preclinical and clinical studies are necessary to further elucidate the underlying biological mechanisms of SRI discontinuation syndrome and to identify the patient populations and agents that are most affected by this phenomenon. Management strategies include gradual tapering of doses and should emphasize clinical monitoring and patient education.

Abstract

Social relationships protect against the development of stress-related psychiatric disorders, yet little is known about the neurobiology that regulates this phenomenon. Recent evidence suggests that oxytocin (OT), a neuropeptide involved in social bond formation, may play a role. This experiment investigated the effects of chronic intranasal OT administration on acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation in adult female squirrel monkeys. Subjects were randomized to one of two experimental conditions. Monkeys were intranasally administered either 50 microg oxytocin (N = 6 monkeys) or 0 microg oxytocin (N = 6 monkeys)/300 microl saline once a day for eight consecutive days. Immediately after drug administration on the eighth day, all monkeys were exposed to acute social isolation. Blood samples for determinations of adrenocorticotropic hormone (ACTH) and cortisol concentrations were collected after 30 and 90 min of stress exposure. Consistent with an anti-stress effect, OT-treated monkeys exhibited lower ACTH concentrations compared to saline-treated monkeys after 90 min of social isolation (F(1,7) = 6.891; P = 0.034). No drug-related differences in cortisol levels were observed, indicating that OT does not directly attenuate the adrenal stress response. Intranasal peptide administration has been shown to penetrate the central nervous system, and research must determine whether intranasally delivered OT exerts its effect(s) at a pituitary and/or brain level. This primate model offers critical opportunities to improve our understanding of the anti-stress effects of OT and may lead to novel pharmacological treatments for stress-related psychiatric disorders.

Abstract

Agitation is both a feature of major depression and a common side effect of antidepressant treatment. Depressive agitation correlates with overall severity of illness and suicide risk, whereas treatment-emergent agitation may contribute to early discontinuation of pharmacotherapy. Thus, agitation merits investigation as a treatment target in clinical depression.In this study, adults with major depression were evaluated for change in agitation and other mood symptoms during adjunctive treatment with divalproex sodium. Twelve patients on antidepressants, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, were given low doses of divalproex sodium and evaluated repeatedly for symptoms of depression, anxiety, and agitation. Agitation severity was evaluated using the Overt Agitation Severity Scale and the Stanford Scale for Agitation Symptoms. Mood symptoms were assessed with the Hamilton Anxiety and the Hamilton Depression Rating Scales.Nine of 12 patients completed 4 weeks of treatment. All agitation scores decreased sharply, whereas depression (Hamilton Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale) symptoms decreased only modestly. Decreased agitation was not merely a function of decreases on the Hamilton Depression or Hamilton Anxiety Rating Scales. Relatively low doses of divalproex sodium appear to be useful in the treatment of agitation associated with major depression.The observation that decreases in agitation were not simply an artifact of overall change in depressive or anxiety symptoms is in keeping with the previous clinical impression that divalproex sodium has a specific effect on depressive agitation. Controlled clinical trials are needed to fully evaluate the utility and symptom specificity of divalproex sodium in depression.

Abstract

We previously reported changes in DA neurochemical estimates after sustained corticosterone (CORT) administration or adrenalectomy (ADX) that are consistent with glucocorticoid-induced inhibition of DA metabolism. The present investigation measured monoamine oxidase type A (MAO-A), type B (MAO-B) and catechol-o-methyltransferase (COMT) activity by enzymatic assay and levels of gene expression by real-time quantitative polymerase chain reaction (rt-PCR) in tissues from sham, ADX, or ADX+CORT-replaced Lewis rats. One week of ADX had no significant effect on either enzyme activity or gene expression for any of the three enzymes examined in the medial prefrontal cortex, striatum, or liver. One week of CORT administration (100mg-21 day release pellet) in ADX rats produced statistically significant decreases in MAO-A enzyme activity and MAO-B gene expression in the liver but no significant changes for any of the three enzymes in either activity or gene expression in the medial prefrontal cortex or striatum. The results do not support inhibition of DA metabolism as a mechanism by which glucocorticoids influence DA-mediated behaviors.

Abstract

The authors investigated the relationship between obstructive sleep apnea/hypopnea (OSAH) and cognition in 36 older adults, 18 APOE epsilon4 carriers, and 18 non-carriers. Greater numbers of respiratory events negatively impacted memory function in epsilon4 carriers only. This is the first study to provide preliminary evidence for a negative interaction of APOE epsilon4 and OSAH on memory in older adults, which may have important implications for treating cognitive decline and delaying dementia onset.

Abstract

This review addresses the question of whether there is evidence that antidepressants are more efficacious than placebo in the treatment of late-life depression and what is the rate of response that physician and patient can expect when antidepressant medication is prescribed in a typical clinical setting. To date, 5 placebo-controlled and 10 comparison trials have study designs of sufficient rigor to provide evidence of antidepressant efficacy and effectiveness in the treatment of late-life depression. The results suggest that antidepressant medications are more effective than placebo. However, placebo-controlled trials are not a simple comparison of only medication versus placebo. Rather, the amount of nonspecific psychosocial interventions included in these trials is considerable and often not systematically measured. Trial design also affects outcome: response and remission rates in comparison trials consistently are 20% to 30% higher than those reported in placebo-controlled trials. Clinical trials do not consistently assess the many moderators that are believed to affect treatment outcome in late-life depression, and therefore, comparisons across studies are problematic because of an inability to determine whether patient samples are truly comparable. For future clinical trials to have maximal relevance, study design should evolve to reflect as closely as possible a typical clinical setting especially with respect to frequency and duration of patient visits.

Abstract

Although various strategies are available to manage nonresponders to an initial treatment for depression, no controlled trials address the utility of switching from an antidepressant medication to psychotherapy or vice versa.To compare the responses of chronically depressed nonresponders to 12 weeks of treatment with either nefazodone or cognitive behavioral analysis system of psychotherapy (CBASP) who were crossed over to the alternate treatment (nefazodone, n = 79; CBASP, n = 61).Crossover trial.Twelve academic outpatient psychiatric centers.There were 140 outpatients with chronic major depressive disorder; 92 (65.7%) were female, 126 (90.0%) were white, and the mean age was 43.1 years. Thirty participants dropped out of the study prematurely, 22 in the nefazodone group and 8 in the CBASP group.Treatment lasted 12 weeks. The dosage of nefazodone was 100 to 600 mg/d; CBASP was provided twice weekly during weeks 1 through 4 and weekly thereafter.The 24-item Hamilton Rating Scale for Depression, administered by raters blinded to treatment, the Clinician Global Impressions-Severity scale, and the 30-item Inventory for Depressive Symptomatology-Self-Report.Analysis of the intent-to-treat sample revealed that both the switch from nefazodone to CBASP and the switch from from CBASP to nefazodone resulted in clinically and statistically significant improvements in symptoms. Neither the rates of response nor the rates of remission were significantly different when the groups of completers were compared. However, the switch to CBASP following nefazodone therapy was associated with significantly less attrition due to adverse events, which may explain the higher intent-to-treat response rate among those crossed over to CBASP (57% vs 42%).Among chronically depressed individuals, CBASP appears to be efficacious for nonresponders to nefazodone, and nefazodone appears to be effective for CBASP nonresponders. A switch from an antidepressant medication to psychotherapy or vice versa appears to be useful for nonresponders to the initial treatment.

Aging and the role of the HPA axis and rhythm in sleep and memory-consolidationAMERICAN JOURNAL OF GERIATRIC PSYCHIATRYBuckley, T. M., Schatzberg, A. F.2005; 13 (5): 344-352

Abstract

Changes in the hypothalamo-pituitary-adrenal (HPA) axis and its rhythm with aging have interesting implications for sleep. Herein, the authors review sleep and HPA changes associated with normal aging and point out the similarities in how they change over time. The authors also discuss the effects of sleep on declarative memory consolidation, in particular. This focused review suggests that some of the declarative memory dysfunction with normal aging, and possibly procedural memory dysfunction, may be partially reversible by instituting methods to augment slow-wave sleep (SWS). Also, agents that decrease nocturnal corticotropin-releasing hormone and the cortisol nadir and enhance SWS may offer potential ways to manipulate the HPA axis/rhythm and improve sleep and memory. In this regard, the authors propose that drugs that act directly on the HPA axis (e.g., mineralocorticoid agonists) may be potentially quite useful for improving both sleep and declarative memory consolidation during sleep.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.

Abstract

Severely stressful early experiences have been implicated in the pathophysiology of psychiatric disorders. In contrast, exposure to mild early life stress (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stressors. Herein we extend this research to examine the effects of mild early life stress on cognition.Squirrel monkeys were randomized to a mild intermittent stress (IS; n = 11) or nonstress (NS; n = 9) condition from 17 to 27 weeks postpartum. At 1.5 years of age, monkeys were assessed for response inhibition on a test previously shown to reflect prefrontal-dependent cognitive function.IS monkeys demonstrated fewer response inhibition errors compared with NS monkeys. There were no rearing-related differences in aspects of performance that did not require inhibitory control. Compared with NS monkeys, IS monkeys had lower basal plasma pituitary-adrenal stress hormone levels. No rearing-related differences on neuroendocrine measures obtained 15 minutes after testing were found.Results from this experiment provide the first evidence that exposure to mildly stressful early experiences improves prefrontal-dependent response inhibition in primates. Combined with our previous data, findings from this animal model suggest that exposure to mild early life stress may enhance the development of brain systems that regulate emotional, neuroendocrine, and cognitive control.

Abstract

To identify the determinants of impaired glucocorticoid receptor (GR) signaling in a model of glucocorticoid resistance, cloned GR from Guyanese squirrel monkeys (gsmGR) was tagged with enhanced green fluorescent protein, and nuclear translocation was examined in transfected COS1 cells. In keeping with evidence that gsmGR transactivational competence is impaired, we found that nuclear translocation is likewise diminished in gsmGR relative to human GR (hGR). Experiments with GR chimeras revealed that replacement of the gsmGR ligand binding domain (LBD) with that from hGR increased translocation. Truncated gsmGR constructs lacking the LDB after amino acid 552 also showed increased translocation even in the absence of cortisol. Three back-mutations of gsmGR to hGR (Thr551Ser, Ala616Ser, and Ser618Ala) in the LBD confirmed that these amino acids play a role in diminished translocation.

Abstract

This randomized pilot study evaluates whether seropositive patients who are randomly assigned to receive a supportive-expressive group therapy plus education intervention show greater improvements in increased immune function and decreased viral load compared to those randomly assigned to an education-only intervention.Fifty-nine individuals who had been HIV-seropositive for at least 6 months prior to inclusion in the study and had been receiving standard pharmacologic treatment were entered in a prospective randomized trial of the effects of weekly supportive-expressive group therapy on changes in immune status. Participants were matched for AIDS status and sex and randomized to receive weekly sessions of group psychotherapy plus educational materials on HIV/AIDS, or to receive the educational materials alone. Participants were assessed before treatment and then 12 weeks later.Individuals who were randomized to group therapy showed a statistically significant increase in CD4 count and decrease in HIV viral load. Among individuals randomized to the education only condition, no significant change occurred in CD4 count or viral load.These results provide preliminary data suggesting that HIV-seropositive individuals who receive supportive-expressive group psychotherapy may experience concomitant improvements in CD4 cell count and viral load. Further research with a larger sample should examine the possible underlying mechanisms of such benefits.

Abstract

While emotional symptoms such as depressed mood and loss of interest have traditionally been considered to constitute the core symptoms of major depressive disorder (MDD), the prevalence and importance of painful physical symptoms such as back pain, abdominal pain, and musculoskeletal pain is becoming increasingly appreciated. Antidepressants possessing dual serotonin/norepinephrine (5-HT/NE) reuptake inhibition may demonstrate greater efficacy in the alleviation of pain. The efficacy of duloxetine, a balanced and potent dual reuptake inhibitor of 5-HT and NE, was evaluated within a cohort of depressed patients with associated painful physical symptoms.In this multicenter, double-blind, placebo-controlled study, patients meeting DSM-IV criteria for MDD were randomized to receive placebo (N=141) or duloxetine 60 mg QD (N=141). Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score 15, a Clinical Global Impression of Severity (CGI-S) score 4, and a Brief Pain Inventory (BPI) Average Pain score 2 at baseline. The primary efficacy measure was the BPI Average Pain score, while secondary measures included other BPI items, the HAMD17 total score, CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQSS). Safety was evaluated by recording treatment-emergent adverse events (spontaneously reported), vital signs, and laboratory analytes.Mean changes in BPI Average Pain for duloxetine- and placebo-treated patients differed significantly at most visits, but only approached significance at endpoint p=0.066. For the main effect of treatment (pooling all visits), significant advantages for duloxetine-treated patients were found in 10 of 11 assessed BPI pain severity and pain interference items, in addition to VAS overall pain and back pain. Mean changes in pain measures for duloxetine-treated patients corresponded to improvements of 25-50%, compared with 19-39% for placebo. Mean changes at endpoint in depression rating scales (HAMD17, CGI-S, PGI-I) did not differ significantly between duloxetine and placebo treatment groups due to unusually high placebo response. The magnitude of placebo treatment effects (as measured by HAMD17 total score and Maier subscale) was significantly smaller in patients with 1 previous depressive episode, compared to those patients with no previous episodes. In patients with 1 previous depressive episode the advantage of duloxetine over placebo was similar to previous studies. Rates of discontinuation due to adverse events were 14.2% vs. 2.1% for duloxetine and placebo, respectively p<0.001. Treatment-emergent adverse events reported at a significantly higher rate by duloxetine-treated patients included nausea, dry mouth, fatigue, and decreased appetite.In this study, duloxetine (60 mg QD) was shown to be an effective treatment for the painful physical symptoms which are frequently associated with depression. Improvements in pain severity occurred independently of changes in depressive symptom severity.

Abstract

The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors.To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression.Double-blind, randomized 8-week study.Eighteen academic and private outpatient clinics.We evaluated 246 cognitively intact patients 65 years or older with major depression.Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122).The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes.Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses.These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

Abstract

This is the first study to examine the prevalence and effects of major depression (MDD) in a sample of adolescent smokers (N = 211) undergoing treatment for nicotine dependence. We assessed MDD at baseline and end of treatment with the mood disorders portion of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Eleven percent of participants reported a history of MDD (6% of males and 21% of females). Study variables did not distinguish those with and without a history of MDD. End of treatment abstinence rates and relapse rates were similar in both groups. Two participants (1%), both female, experienced onset of MDD during the treatment. The findings provide further evidence that MDD is a comparatively common disorder among children and adolescents and that clinicians should monitor and be prepared to respond to depression that may emerge during the treatment of nicotine-dependent adolescents.

Abstract

Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.

Abstract

Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine. Premenopausal women (n = 20) who met criteria for major depression with no other confounding Axis I disorders, medications, or medical illnesses and were not taking hormonal contraceptives were evaluated with an evening metyrapone challenge before the onset of treatment. Twenty-one normal women were also studied with the evening metyrapone challenge. The depressed patients then entered an open label treatment with fluoxetine for 6 weeks. Subjects were classified as responders if they demonstrated a 50% or greater decrease in Hamilton Depression Rating Scale rating. As a group, the depressed women demonstrated significantly increased ACTH secretion compared to control women before the onset of treatment, during the metyrapone challenge. Before treatment, women who were non-responders to fluoxetine showed increased HPA axis activation compared to controls, while the fluoxetine responders did not differ significantly from normal subjects in their ACTH levels during metyrapone challenge. These results suggest that overactivity of the HPA axis may be one factor associated with slower response to fluoxetine. This may reflect the greater severity of subjects with HPA axis dysregulation or the need to normalize the HPA axis with medications for optimal response.

Abstract

Adolescent smokers (N = 211) were randomized to 1 of 2 groups: (a) nicotine patch plus bupropion SR (sustained release; 150 mg per day) or (b) nicotine patch plus placebo. Group skills training sessions were conducted each week by research staff. Abstinence rates at Weeks 10 and 26 were as follows: (a) patch plus bupropion, 23% and 8%, (b) patch plus placebo, 28% and 7%. Despite the lack of a treatment effect, a large majority of adolescents in both treatment groups reduced their consumption to a few cigarettes per day or less and maintained this reduction over time. Similarly, an examination of survival curves revealed that by the end of treatment many had managed to avoid a return to daily smoking. These findings are encouraging and suggest new avenues for research. For example, treatments of the kind examined in this report, augmented by extended maintenance therapies, may yield higher long-term success rates.

Abstract

The purpose of this study was to compare the efficacy and safety of olanzapine (OLZ) monotherapy and an olanzapine/fluoxetine combination (OFC) with placebo (PLA) for unipolar major depression with psychotic features. Under a single protocol, two 8-week, double-blind trials were conducted at 27 sites. Patients (n = 124 trial 1, n = 125 trial 2) were randomized to 1 of 3 treatment groups: OLZ (5 to 20 mg/d), PLA, or OFC (olanzapine 5 to 20 mg/d + fluoxetine 20 to 80 mg/d). The primary outcome measure was the 24-item Hamilton Depression Rating Scale total score. For trial 1, endpoint improvement for the OLZ group (-14.9) was not significantly different from the PLA or OFC groups. The OFC group had significantly greater endpoint improvement (-20.9) than the PLA group (-10.4, P = 0.001); this significant difference was present within 7 days of therapy and maintained at every subsequent visit. The OFC group also had significantly higher response rate (63.6%) than the PLA (28.0%, P = 0.004) or OLZ (34.9%, P = 0.027) groups. For trial 2, there were no significant differences among treatment groups on the 24-item Hamilton Depression Rating Scale total scores or response rates. The combination exhibited a comparable safety profile with OLZ monotherapy and no significant increases in extrapyramidal symptoms compared with placebo. Patients with major depression with psychotic features treated with OLZ monotherapy did not demonstrate significant depressive symptom improvement compared with placebo in either trial; however, an olanzapine/fluoxetine combination was associated with significant improvement compared with placebo in one trial and was well tolerated.

Abstract

Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

Abstract

Neuropsychological functioning has been a focus of study in psychotic disorders for many decades. These studies have focused primarily on schizophrenia, and less so on the affective psychoses, including psychotic major depression PMD. Several studies have provided evidence of cognitive dysfunction in PMD. However, these studies have utilized different assessment methods and instruments. Consequently, a clear picture of the nature and severity of cognitive impairment in PMD has yet to emerge in the literature. The current review seeks to provide a summary of the literature by composing a quantitative and qualitative review of the research to date on the cognitive impairment in psychotic major depression, specifically as it contrasts to those deficits observed in nonpsychotic depression. This review also provides a summary model of the pathophysiology of PMD to provide the necessary context to understanding the biological mechanisms of these impairments.

Abstract

Mechanisms of action, onset and duration of action, and interactions with other medications--all of these pharmacokinetic properties of pharmacologic agents affect the efficacy and safety of therapeutic regimens for bipolar disorder. For example, antiglutamatergic agents such as lamotrigine may relieve depression but have no impact on mania. Atypical antipsychotics with the dual effect of blocking dopamine and serotonin receptors in the brain decrease psychosis, mania, and, according to some preliminary indications, possibly depression. The impact of these properties has been borne out in clinical studies. Mood stabilizers such as lithium and valproate stabilize mood by significantly decreasing the manic and hypomanic symptoms of bipolar disorder, although they can have effects on depressive symptoms too. Lamotrigine stabilizes mood by reducing depression. The atypical anti-psychotics have been shown to be effective either as monotherapy or in combination with mood stabilizers.

Abstract

Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma.

Abstract

The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect).An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood.Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication.Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

Abstract

Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response.The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping.Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age.The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.

Abstract

As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.

Abstract

Early emotional experiences affect developing brain systems that subsequently mediate adult learning and memory in rodents. Here we test for similar effects in squirrel monkeys (Saimiri sciureus) four years after disruptions in early maternal availability. These conditions were previously shown to generate differences in emotional behavior, hypothalamic-pituitary-adrenal stress physiology, and right ventral medial prefrontal volumes determined in adulthood by magnetic resonance imaging. This report identifies in the same monkeys variability in reward-related memory on tests with a spatial reversal. Adult monkeys that more often selected locations repeatedly rewarded before each reversal had larger right ventral medial prefrontal volumes, but not hippocampal nor dorsolateral prefrontal volumes on the left or right brain side. Differences in performance were also discerned after each spatial reversal. These findings indicate that maternal availability alters developing ventral medial prefrontal brain regions involved in reward-related memory.

Abstract

We monitored the emergence of major depression (MDD) during treatment for nicotine dependence among 224 smokers. MDD was assessed on three occasions during the course of treatment with the mood disorders portion of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID), fourth edition (DSM-IV). Out of 224 participants, 20% had suffered a past episode of MDD, 18% of males and 22% of females. Four percent (n=10) experienced onset of MDD during the course of the study, four males and six females. Only 2 of the 10 cases managed to achieve abstinence at end of treatment. Those who reported large increases in depression symptoms between baseline and end of treatment (Week 10) were less likely to be abstinent at 26-week follow-up. The evidence indicates that those who treat nicotine dependence must be prepared to monitor and respond to the emergence of depression associated with treatment.

Abstract

Many patients fail to achieve an adequate response to a given antidepressant trial. The best-studied augmentation agents, lithium and thyroid supplementation are less commonly used. Augmenting antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Several case reports and 2 open label studies suggest efficacy of this strategy. The purpose of this study is to further examine the utility of bupropion sustained release (SR) augmentation in patients with inadequate response to selective serotonin reuptake inhibitors. Patients who met DSM-IV criteria for major depression and had failed to achieve adequate response to an SSRI were considered for this study. Eligible patients were required to have a score of 16 on the 24-item Hamilton Depression Rating Scale (HDRS). Patients were treated openly for 6 weeks with bupropion SR added to their existing antidepressant. The dose range of bupropion was 150 to 300 mg per day. At each visit, patients were assessed using the Beck Depression Inventory (BDI), the Hamilton Depression Ratings Scale (HDRS), and the Clinical Global Impression (CGI). Twenty-eight patients (12 men, 16 women) entered the study. Twenty-five patients completed the six-week trial. With respect to the clinical benefit of bupropion SR augmentation, 15 out of 28, or 54% of patients, were classified as responders, showing a decrease in their HDRS or BDI scores of 50% or more between baseline and Week 6. This prospective, open-label trial supports the use of bupropion SR in the augmentation of SSRIs and venlafaxine. Placebo controlled trials should be completed to further evaluate the efficacy of this strategy.

Abstract

Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.

Using chronic pain to predict depressive morbidity in the general populationARCHIVES OF GENERAL PSYCHIATRYOhayon, M. M., Schatzberg, A. F.2003; 60 (1): 39-47

Abstract

Pain syndrome is thought to play a role in depression. This study assesses the prevalence of chronic (>or= 6 months' duration) painful physical conditions (CPPCs) (joint/articular, limb, or back pain, headaches, or gastrointestinal diseases) and their relationship with major depressive disorder.We conducted a cross-sectional telephone survey of a random sample of 18 980 subjects from 15 to 100 years old representative of the general populations of the United Kingdom, Germany, Italy, Portugal, and Spain. Answers provided during telephone interviews using the Sleep-EVAL system were the main outcome measure. Interviews included questions about mental disorders and medical conditions. Data on painful physical conditions were obtained through questions about medical treatment, consultations, and/or hospitalizations for medical conditions and a list of 42 diseases.Of all subjects interviewed, 17.1% reported having at least 1 CPPC (95% confidence interval [CI], 16.5%-17.6%). At least 1 depressive symptom (sadness, depression, hopelessness, loss of interest, or lack of pleasure) was present in 16.5% of subjects (95% CI, 16.0%-17.1%); 27.6% of these subjects had at least 1 CPPC. Major depressive disorder was diagnosed in 4.0% of subjects; 43.4% of these subjects had at least 1 CPPC, which was 4 times more often than in subjects without major depressive disorder (odds ratio [OR], 4.0; 95% CI, 3.5-4.7). In a logistic regression model, CPPC was strongly associated with major depressive disorder (OR: CPPC alone, 3.6; CPPC + nonpainful medical condition, 5.2); 24-hour presence of pain made an independent contribution to major depressive disorder diagnosis (OR, 1.6).The presence of CPPCs increases the duration of depressive mood. Patients seeking consultation for a CPPC should be systematically evaluated for depression.

Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorderMeeting on Achieving Depression RemissionSchatzberg, A. F.PHYSICIANS POSTGRADUATE PRESS.2003: 30–37

Abstract

Although highly selective antidepressants such as the selective serotonin reuptake inhibitors represent an advance over older drugs with respect to tolerability, they are not more effective than previous agents. Antidepressants that enhance transmission in more than one monoamine system may have greater efficacy than highly selective drugs, while equaling or improving their adverse effect profiles. This article reviews the properties of duloxetine, a potent and balanced inhibitor of norepinephrine and serotonin reuptake. Controlled studies indicate a high degree of efficacy, tolerability, and safety for duloxetine in the treatment of major depressive disorder. In particular, rapid therapeutic onset and high remission rates have been noted. Duloxetine appears to have significant benefit in the treatment of the painful physical symptoms associated with depression. The continued presence of such symptoms may predict relapse. Accordingly, it is hoped that duloxetine therapy may reduce the likelihood of depressive relapse.

Abstract

Major depression with psychotic features, while fairly common, is frequently misdiagnosed. Symptoms seen in these patients are those of an overall severe depressive disorder with psychomotor impairment (retardation or agitation), guilt, suicidal preoccupation, and neuropsychological impairment. A number of biological characteristics and behavioral symptoms are specific to patients suffering from psychotic depression and differ significantly from those of nonpsychotic depression. Psychotic depression is seen in patients of all ages, and it has a high short-term morbidity and risk of suicide. Data support the use of antipsychotics in combination with antidepressants for major depression with psychotic features, but other treatments may have as great or greater efficacy for the disorder. This article focuses on recognizing the features of psychotic depression, the success of current treatment options, and new treatments under investigation.

Abstract

A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

Abstract

The effects of alterations in peripheral corticosterone levels on multiple dopamine neurochemical estimates were examined in inbred Fischer and Lewis inbred rat strains. 2x2 ANOVA's (treatment x strain) showed a main effect for treatment (1 week CORT versus placebo) on the concentrations of the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid in the medial prefrontal cortex, with lower levels after treatment, but no significant treatment versus strain interaction. There was no effect of CORT treatment on DA metabolites in the nucleus accumbens shell or dorsal striatum. DOPA accumulation in any terminal region examined and tyrosine hydroxylase protein content in the ventral tegmental area were also not affected by 1 week of corticosterone in either strain. One week after adrenalectomy, homovanillic acid but not dihydroxyphenylacetic acid concentrations were significantly increased in the medial prefrontal cortex, dorsal striatum, and nucleus accumbens shell in the Lewis but not the Fischer strain, with a significant treatment x strain interaction only in the dorsal striatum. Based on these findings, the effect of adrenalectomy on DOPA accumulation and extracellular DA concentrations was examined in the Lewis strain only. Adrenalectomy produced a decrease in DOPA accumulation in the dorsal striatum with no significant change in the other regions. Adrenalectomy did not alter estimates of extracellular dopamine concentrations determined by in vivo no net flux microdialysis but did significantly increase in vivo dopamine recovery in the dorsal striatum. The findings indicate a pattern of changes in neurochemical measurements consistent with a small magnitude inhibition of basal dopamine metabolism, but not with a change neuronal activity, release or reuptake.

Prevalence of depressive episodes with psychotic features in the general populationAMERICAN JOURNAL OF PSYCHIATRYOhayon, M. M., Schatzberg, A. F.2002; 159 (11): 1855-1861

Abstract

The study evaluated the prevalence of major depressive episodes with psychotic features in the general population and sought to determine which depressive symptoms are most frequently associated with psychotic features.The sample was composed of 18,980 subjects aged 15-100 years who were representative of the general populations of the United Kingdom, Germany, Italy, Portugal, and Spain. The participants were interviewed by telephone by using the Sleep-EVAL system. The questionnaire included a series of questions about depressive disorders, delusions, and hallucinations.Overall, 16.5% of the sample reported at least one depressive symptom at the time of the interview. Among these subjects, 12.5% had either delusions or hallucinations. More than 10% of the subjects who reported feelings of worthlessness or guilt and suicidal thoughts also had delusions. Feelings of worthlessness or guilt were also associated with high rates of hallucinations (9.7%) and combinations of hallucinations and delusions (4.5%). The current prevalence of major depressive episode with psychotic features was 0.4% (95% CI=0.35%-0.54%), and the prevalence of a current major depressive episode without psychotic features was 2.0% (95% CI=1.9%-2.1%), with higher rates in women than in men. In all, 18.5% of the subjects who fulfilled the criteria for a major depressive episode had psychotic features. Past consultations for treatment of depression were more common in depressed subjects with psychotic features than in depressed subjects with no psychotic features.Major depressive episodes with psychotic features are relatively frequent in the general population, affecting four of 1,000 individuals. Feelings of worthlessness or guilt can be a good indicator of the presence of psychotic features.

Abstract

Theories of human development suggest that experiences embedded in social relationships alter prefrontal brain systems that mediate emotional self-regulation. This study tests for experience-dependent effects on prefrontal gray and white matter volumes determined in 39 young adult monkeys (Saimiri sciureus) 4 years after conditions that modified early maternal availability. These conditions were previously shown to alter subsequent measures of emotional behavior, social propensities, and hypothalamic-pituitary-adrenal axis stress physiology. Here we identify significant differences in right but not left adult prefrontal volumes, with experience-dependent asymmetric variation most clearly expressed in ventral medial cortex measured in vivo by magnetic resonance imaging (MRI). Follow-up studies now need to determine whether maternal availability directly affects or interacts with subsequent experiences to alter prefrontal substrates of emotional processing and sensitivity to stress.

Abstract

>55% were observed in two of the studies, while in a third study the probability of remission with duloxetine treatment was nearly three times that observed with placebo (44% versus 16%). Duloxetine also produced significant improvement in painful physical symptoms compared with placebo, in many cases after only 2 weeks of treatment. The discontinuation rate due to adverse events (14.6%) was similar to those observed with selective serotonin reuptake inhibitors. The most frequently reported adverse events were nausea, dry mouth, fatigue, and insomnia. Conclusion. Duloxetine was demonstrated to be safe and effective in the treatment of MDD. The starting dose with the best balance of efficacy and tolerability is 60 mg QD.

Abstract

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Abstract

Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks).Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events.Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events.During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.

Abstract

The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained.Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days.All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group.These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.

Abstract

The authors discuss 6 challenges facing the recruitment and retention of physician scientists as career mental health researchers. These challenges include (1) early identification and recruitment at the undergraduate and medical student level; (2) recruitment of a more diverse group of trainees; (3) safety nets for reducing attrition; (4) strategies to promote successful competition for K awards; (5) definition of appropriate roles and career development opportunities in multisite clinical trials; and (6) strategies for the mentoring "cost." A coalition of stakeholders--federal, academic, foundational, and in the pharmaceutical industry--is needed to meet these challenges.

Abstract

Both noradrenaline (NA) and serotonin (5-HT) appear to be involved in depression. Evidence suggests that dual-acting antidepressants, i.e. those that affect both monoamine systems, such as tricyclic antidepressants and the noradrenergic and specific serotonergic antidepressant mirtazapine, may have greater efficacy and a faster onset of action than drugs that act on a single monoamine system only, such as the selective serotonin reuptake inhibitors (SSRIs). Cell firing is reduced by SSRIs in the short-term, but is increased by mirtazapine, probably due to its actions on both NA (via alpha(2) antagonism) and 5-HT (via alpha(1)-stimulation by NA). This may help to explain clinical evidence suggesting that mirtazapine has a faster onset of action than the more selective antidepressants.

Abstract

Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated.To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder.Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States.Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20.Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks.Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores.On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo.This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.

Abstract

Episodic and semantic memory are two forms of declarative memory which appear to function in distinct yet interdependent ways. Here we provide direct evidence for a functional relationship between these two memory systems by showing that left lateral temporal lobe regions involved in semantic memory play an important role in accurate episodic memory retrieval.

Abstract

Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes.Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging.Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size.In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.

Abstract

The theory that psychotic major depression is a distinct syndrome is supported by reports of statistically significant differences between psychotic and nonpsychotic major depression in presenting features, biological measures, familial transmission, course and outcome, and response to treatment. This study examined differences in performance on a verbal memory test and in cortisol levels between patients with psychotic and nonpsychotic major depression and healthy volunteers.Ten patients with psychotic major depression, 17 patients with nonpsychotic major depression, and 10 healthy volunteers were administered the Wallach Memory Recognition Test and had blood drawn at half-hour intervals over the course of an afternoon to assay cortisol levels.Subjects with psychotic major depression had a higher rate of errors of commission on the verbal memory test (incorrectly identified distracters as targets) than did subjects with nonpsychotic major depression or healthy volunteers; errors of omission were similar among the three groups. Subjects with psychotic major depression had higher cortisol levels throughout the afternoon than subjects with nonpsychotic major depression or healthy volunteers. This effect became even more pronounced later in the afternoon.Psychotic major depression is endocrinologically different from nonpsychotic major depression and produces cognitive changes distinct from those seen in nonpsychotic major depression.

Abstract

The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.

Abstract

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.

Abstract

Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study.After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment.Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment.The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates.Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Abstract

The brain is a major target organ for corticosteroids. It has been observed that excessive circulatory levels of endogenous and exogenous corticosteroids are frequently associated with cognitive impairment in a wide variety of clinical disease states. Cognition and low levels of corticosteroids have been less well studied. In this paper we review the literature on glucocorticosteroid effects on cognition and delineate specific functions that appear to be causally affected. We draw a possible connection to specific areas of brain perturbation, including the hippocampus and frontal lobe regions. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced.

Abstract

Corticosteroids have been implicated in hippocampal atrophy in patients with severe psychiatric disorders, but little is known about receptor expression for corticosteroids in human or nonhuman primate brain. Both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were surveyed in this study of squirrel monkey brain using in situ hybridization histochemistry. Regions of high GR mRNA levels included CA1 and CA2 of hippocampus, dentate gyrus, paraventricular hypothalamus, lateral geniculate, lateral>medial amygdala, and cerebellum. Western analysis confirmed that GR immunoreactivity in squirrel monkey brain tissue most likely reflects the alpha isoform. Regions of high MR mRNA levels included all hippocampal pyramidal cell fields, dentate gyrus granule cell layer, lateral septum, medial>lateral amygdala, and to a lesser extent, cerebellum. Low levels of MR were also expressed in caudate and putamen. Receptor expression for corticosteroids in deep brain structures and the hippocampal formation was similar to that previously reported in rodents, but GR and MR mRNA were expressed at higher levels in squirrel monkey cerebral cortex. GR expression was evident in all cortical layers, particularly the pyramidal cell-rich layers II/III and V. MR expression was restricted to the more superficial cortical layers, and was only moderately represented in layer V. Laminar patterns were apparent in all regions of cortex for GR expression in squirrel monkeys, but low MR mRNA levels were found in dorsomedial prefrontal cortex (PFC). Different subregional distributions and distinctive laminar patterns suggest specialized functions or coordinated interactions between GR and MR mediated functions in primate PFC.

Abstract

Most studies of cortisol-induced cognitive impairments have focused on hippocampal-dependent memory. This study investigates a different aspect of cognition in a randomized placebo-controlled experiment with monkeys that were treated with cortisol according to a protocol that simulates a prolonged stress response. Young adult and older adult monkeys were assigned randomly to placebo or chronic treatment with cortisol in a 2 x 2 factorial design (n = 8 monkeys per condition). Inhibitory control of behavior was assessed with a test shown previously in primates to reflect prefrontal cortical dysfunction. Failure to inhibit a specific goal-directed response was evident more often in older adults. Treatment with cortisol increased this propensity in both older and young adult monkeys. Age-related differences in response inhibition were consistent across blocks of repeated test trials, but the treatment effects were clearly expressed only after prolonged exposure to cortisol. Aspects of performance that did not require inhibition were not altered by age or treatment with cortisol, which concurs with effects on response inhibition rather than nonspecific changes in behavior. These findings lend support to related reports that cortisol-induced disruptions in prefrontal dopamine neurotransmission may contribute to deficits in response inhibition and play a role in cognitive impairments associated with endogenous hypercortisolism in humans.

Abstract

Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.

Abstract

Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients.Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours.Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices.In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.

Abstract

The primary objective of this investigation was to examine the acute antidepressant effects of intravenous hydrocortisone and ovine corticotropin releasing hormone (CRH) infusions in patients with major depression.Twenty-two patients who met DSM-III-R criteria for nonpsychotic major depression were randomly assigned to receive intravenously 1 mg/kg of ovine CRH, 15 mg of hydrocortisone, or saline under double-blind conditions on day 1. Standard depression rating scales were completed on day 1 before the study medications were administered and again the following day (day 2).Patients treated with hydrocortisone demonstrated a significantly greater reduction in total 21-item Hamilton Depression Rating Scale scores (mean reduction=8.4 points or 37%) than patients given ovine CRH (mean=1.2 points) or placebo (mean=1.3 points).Acute hydrocortisone infusion is associated with a rapid and robust reduction in depressive symptoms. The authors discuss the therapeutic implications of these findings.

Abstract

At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions.A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale.Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test).These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.

Abstract

To examine the efficacy of cognitive-behavioral group therapy for adolescents (CBGT-A) in females with social phobia and the effect of this treatment on the risk for major depression.Female adolescents with social phobia (N = 35) were randomly assigned to treatment (n = 12) or no treatment (n = 23) groups. Assessments were conducted at baseline, after treatment, and at a 1-year follow-up.Eleven subjects completed treatment. Sixteen weeks of treatment produced a significant improvement in interference and reduction in symptoms of social anxiety. There was a significant reduction in the number of subjects meeting DSM-IV criteria for social phobia in the CBGT-A versus the untreated group; however, at the 1-year follow-up there were no significant differences by treatment condition. There was also suggestive evidence that treatment of social phobia lowers the risk for relapse of major depression among those with a history of major depression. Combining social phobia and major depression as the outcome produced more robust treatment effects in the 1-year follow-up.This pilot study provides evidence for a moderate short-term effect of CBGT-A for treating female adolescents suffering from social phobia and indicates that treatment of social phobia may result in a reduction of major depression.

Abstract

The efficacy of clozapine was examined in a group of patients with treatment-refractory bipolar disorder, manic type with psychotic features.Twenty-two subjects with treatment-refractory bipolar disorder with active manic and psychotic symptoms participated in a 12-week open-label trial of clozapine. After a 2-10-day drug washout period, patients began treatment with clozapine at 25 mg/day; the dose was increased 25 mg/day (as tolerated) to a maximum level of 550 mg/day. Patients were evaluated longitudinally over the course of the study with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale, and the Clinical Global Impressions (CGI) scale.Fourteen of the 22 subjects in the study continued taking clozapine for at least 10 of the 12 weeks. Among the entire group, mean improvements of 56. 7%, 56.6%, and 39.1% were seen on the BPRS, Young Mania Rating Scale, and CGI, respectively. Seventeen of the 22 subjects (77.3%) experienced at least a 20% improvement in scores on all three scales.The findings from this open-label study, which are consistent with previous retrospective studies, case reports, and one other open-label prospective study, suggest that clozapine is an effective agent for patients with treatment-refractory psychotic mania.

Abstract

Double-blind, random-assignment placebo-controlled trials are routinely used in evaluating efficacy of potential antidepressant agents. In recent years concern has risen that placebo response rates in unipolar depression are too high, and this has eroded confidence in both old and new agents. At the same time, the use of placebos has been questioned by patients and their advocates. We review factors that have been commonly explored as associated with placebo response (e.g., length of episode, severity, subtype), as well as issues in methodology (e.g., interrater reliability, statistical artifacts). We discuss possible methods of dealing with the problem of placebo response, emphasizing reconceptualizing effect sizes to design more powerful single trials and a systematic sequence of trials to achieve the right answers.

Abstract

This article reviews the available data on social functioning in depression and provides clinical guidelines and opinion on this important and expanding field.A MEDLINE search was conducted to identify all English-language articles (1988-1999) using the search terms depression and social functioning, depression and social adjustment, depression and psychosocial functioning, and social functioning and antidepressant. Further articles were obtained from the bibliographies of relevant articles.Depressive disorders are frequently associated with significant and pervasive impairments in social functioning, often substantially worse than those experienced by patients with other chronic medical conditions. The enormous personal, social, and economic impact of depression, due in no small part to the associated impairments in social functioning, is often underappreciated. Both pharmacologic and psychotherapeutic approaches can improve social impairments, although there is a lack of extended, randomized controlled trials in this area using consistent assessment criteria.Despite this lack, it is becoming clear that not all treatments are equally effective in relieving the impaired social functioning associated with depressive disorders. Furthermore, efficacy in relieving the core symptoms of depression does not necessarily guarantee efficacy in relieving impaired social functioning.

Abstract

Squirrel monkeys are among a diverse group of New World primates that demonstrate unusually high levels of circulating corticosteroids and glucocorticoid receptor (GR) insensitivity. Recent evidence suggests that overexpression of an immunophilin impairs dexamethasone binding to GR in the Bolivian squirrel monkey (Saimiri boliviensis). Here we describe the cloning, expression, and functional characterization of GR from the closely related Guyanese squirrel monkey (S. sciureus). The cloned Guyanese squirrel monkey GR (gsmGR) cDNA closely resembles human GR (hGR) cDNA, and yields a high affinity dexamethasone binding receptor when expressed in COS-1 cells. Transactivation analysis of hGR and gsmGR expressed in CV-1 cells and cultured squirrel monkey kidney (SMK) cells indicates that: (1) SMK cells elaborate a functional high activity GR from human GR cDNA; (2) gsmGR is an order of magnitude less efficient than hGR at transactivation in CV-1 and SMK cells; and (3) maximal transactivation by gsmGR is attenuated in both cell lines. Glucocorticoid resistance in S. sciureus is at least partly attributable to a naturally occurring mutation in the GR gene that results in impaired GR transactivation.

Abstract

A 17-year-old, 1-kg, colony-housed, male squirrel monkey (Samiri sciureus) developed clinical signs of congestive heart failure. The monkey presented with lethargy, increased heart and respiratory rates, and mild abdominal distention. The clinical history, laboratory analysis, and radiographic findings were consistent with heart failure due to dilative cardiomyopathy. Gross and microscopic examination of the heart confirmed a dilative cardiomyopathy. This is the first report describing congestive heart failure caused by dilative cardiomyopathy in a squirrel monkey. Spontaneous dilative cardiomyopathy may be infrequently observed in the squirrel monkeys because they are not routinely housed in the research environment during their advancing years.

Clinical efficacy of reboxetine in major depressionSymposium on Norepinephrine: Neurotransmitter for the Millennium held in Conjunction with the 152nd Annual Meeting of the American-Psychiatric-AssociationSchatzberg, A. F.PHYSICIANS POSTGRADUATE PRESS.2000: 31–38

Abstract

The past decade has witnessed the advent of selective serotonin reuptake inhibitors (SSRIs) as first-line treatments for major depression. Still, there is considerable debate as to whether these agents are as effective or as potent as the first-generation tricyclic antidepressants (TCAs) or the mixed reuptake inhibitor, venlafaxine, all of which exert considerable effect on norepinephrine (NE) reuptake. Recently, reboxetine, a selective NE reuptake inhibitor (selective NRI), has been introduced in Europe. This drug has only a minimal affinity for muscarinic acetylcholine receptors and therefore causes less dry mouth, constipation, or other such effects than do the TCAs. Reboxetine does not block serotonin reuptake or alpha1 receptors and, thus, does not appear to produce significant nausea, diarrhea, or hypotension. Unlike other antidepressants, reboxetine appears to be nonsedating. Data on acute and long-term clinical efficacy and safety from double-blind, placebo-controlled, and active comparator studies with reboxetine are reviewed. These studies indicate that reboxetine is significantly more effective than placebo and as effective as fluoxetine in reducing depressive symptoms. Improvements in social adjustments were reported to be more favorable with reboxetine than with fluoxetine. Further, data from controlled clinical trials have shown that the side effect profile for reboxetine is relatively benign. The clinical implications of studies on reboxetine are discussed with an eye toward understanding the potential role NE reuptake blockers may play in the treatment of patients with major depression.

New indications for antidepressantsRoundtable Conference on New Strategies for Improving the Treatment of DepressionSchatzberg, A. F.PHYSICIANS POSTGRADUATE PRESS.2000: 9–17

Abstract

The second and third generation of antidepressants, i.e., the selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine, are proving to be useful in a variety of seemingly diverse disorders, including most anxiety disorders. In addition to receiving approval from the U.S. Food and Drug Administration (FDA) for major depressive disorder, some of the newer antidepressants have received FDA approval for other disorders, e.g., generalized anxiety disorder (venlafaxine), bulimia nervosa (fluoxetine), obsessive-compulsive disorder (fluvoxamine, paroxetine, sertraline, and fluoxetine), social phobia (paroxetine), panic disorder (sertraline, paroxetine), and posttraumatic stress disorder (sertraline). In controlled studies, these agents have also shown usefulness in premenstrual dysphoric disorder, borderline personality disorder, obesity, smoking cessation, and alcoholism. This article describes the new and potential indications for recently developed antidepressants and the studies that suggested these indications.

Abstract

Most nonhuman primate research on risk factors underlying vulnerability to stress has focused on early psychosocial experiences in various species of macaques. To test for genetic and experiential effects on emotional vulnerability in randomly bred squirrel monkeys, here we combined a paternal half-sibling analysis with three postnatal rearing protocols that altered aspects of maternal availability. In one condition offspring were periodically removed from natal groups, whereas differences in maternal availability were produced in two other conditions by manipulating the effort required of lactating mothers to successfully locate food. After completion of these protocols at 21 weeks of age, social affinities, maternal separation induced peep-calls, and plasma levels of cortisol were assessed from 29 to 37 weeks of age. Significant postnatal rearing effects and the lowest heritabilities were detected in peak elevations of cortisol measured 1 day after the removal of mothers from otherwise undisturbed groups. Individual differences in cortisol 3-7 days later revealed negligible postnatal rearing effects and the highest heritabilities (h(2) approximately. 70), as offspring sired by certain fathers failed to return to the preseparation level found in undisturbed natal groups. Paternal half-siblings that responded with long lasting increases in cortisol spent more time near their mother in undisturbed groups and exhibited long-lasting increases in separation induced peep-calls. These findings concur with human twin studies that suggest genetic and experiential factors contribute to individual differences in vulnerability to emotional distress.

Abstract

Differences in the behavioral responses of Lewis and Fischer (F344) inbred rat strains to stress and psychoactive drugs have been related to differences in the expression of various regulatory proteins in regions containing mesolimbic dopamine (DA) neurons. The present study compared basal and stimulated neurochemical estimates of DA utilization and synthesis in mesocortical, mesolimbic and nigrostriatal DA terminal regions of these two strains. In unstressed control animals, the Lewis strain had lower DA concentrations in the dorsal striatum (ST; 80.3% of F344) and lower basal dihydroxyphenylalanine (DOPA) accumulation after m-hydroxybenzylhydrazine (NSD 1015) treatment in the medial prefrontal cortex (mPfx; 75.3% of F344). Similar differences were observed in vehicle-injected animals. No strain differences in basal neurochemistry were apparent in the nucleus accumbens shell (NAs) or core (NAc). In response to restraint stress, dihydroxyphenylacetic acid (DOPAC) to DA ratios in the mPfx, NAs and ST increased in the F344 but not the Lewis strain. However, restraint stress did not significantly increase DOPA accumulation in the F344 strain. This latter finding was not due to a deficit in synthesis capacity, as gamma-hydroxybutyric acid lactone (GBL) increased DOPA accumulation significantly more in F344 than Lewis animals. Finally, haloperidol increased DA utilization similarly in the two strains. Together these findings suggest that the inbred, behaviorally divergent F344 and Lewis rats have selective differences in mesocortical, nigrostriatal and mesolimbic DA neuronal regulation.

Abstract

When separated from groups, squirrel monkeys respond with significant increases in plasma cortisol and adrenocorticotropic hormone (ACTH). While cortisol remains elevated above pre-separation levels, significant reductions occur in ACTH. Monkeys that respond with greater increases in cortisol subsequently exhibit greater reductions in ACTH, which suggests that reductions in ACTH are mediated by corticosteroid feedback. Monkeys that respond with greater increases in cortisol also tend to exhibit greater cerebrospinal fluid levels of the dopamine metabolite HVA, but not the norepinephrine metabolite MHPG, or corticotropin-releasing factor (CRF). Attenuation of corticosteroid feedback with metyrapone results in significant increases in circulating ACTH, and in older monkeys increases plasma HVA. Similar findings in humans have been reported in clinical studies of hypercortisolism and major depression.

Phenomenology and treatment of agitationClosed Symposium on the Phenomenology and Treatment of Agression Across Psychiatric IllnessesSchatzberg, A. F., Debattista, C.PHYSICIANS POSTGRADUATE PRESS.1999: 17–20

Abstract

Agitation is a troublesome, common symptom in major depression that can be difficult to manage. It is sometimes a side effect of antidepressant treatment and may occasionally represent a mixed bipolar episode. If agitation fails to respond to an antidepressant alone, treatment may be augmented with a benzodiazepine, a neuroleptic, or lithium. Preliminary evidence indicates that divalproex, which has been found useful for bipolar disorder and for agitation associated with Alzheimer's disease, may also be effective for agitated depression. A controlled trial is now underway.

Abstract

This study examined the validity of the early-late onset subtyping distinction in dysthymic disorder.Participants were 340 out-patients meeting DSM-III-R criteria for dysthymia and a concurrent major depressive episode (MDE). The sample was drawn from a 12-site double-blind randomized parallel group trial comparing the efficacy of sertraline and imipramine in the treatment of chronic depression. All patients received comprehensive evaluations using semi-structured interviews and rating scales.73% of the sample met criteria for the early-onset, and 27% for the late-onset, subtype. The early-onset patients had a significantly longer index MDE, significantly higher rates of personality disorders and lifetime substance use disorders, and a significantly greater proportion had a family history of mood disorder. The subgroups did not differ in symptom severity or functional impairment at baseline, nor in response to a 12-week trial of antidepressants.Further work is needed to extend these findings to dysthymic disorder without superimposed MDEs.These results support the distinction between early-onset and late-onset dysthymic disorder.

Abstract

While outcome has improved in patients with depressive disorders since the introduction of the newer antidepressants, some physicians still treat severely depressed patients with the older tricyclic antidepressants because of conflicting reports about the efficacy of the newer agents, particularly the selective serotonin reuptake inhibitors, in severe depression. However, a standardized operational definition of severe depression is lacking, and treatment studies are difficult to evaluate due to variation in methodology. Remission rates are relatively low in many of the short-term clinical trials of the newer antidepressants in severe depression, but may improve if the research design were to include a longer trial and aggressive dosing. There is some evidence that venlafaxine, a serotonin-norepinephrine antidepressant, may offer some advantage for severely depressed patients.

Abstract

Anxiety disorders such as social phobia (SP) often have their onset during adolescence and frequently precede the onset of major depression. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is well-documented in major depression. Consequently, there is considerable interest in HPA function in anxiety disorders. We examined salivary cortisol levels in 27 SP adolescent girls and 21 matched controls during normal daily activities, and immediately before and after a modified Trier Social Stress Test (TSST). Both SP subjects and controls showed significant elevations in cortisol levels prior to the TSST, and prior to attending school. These results suggest that salivary cortisol is a sensitive measure of anticipatory anxiety, but we failed to find significant differences between SP subjects and controls.

Abstract

It has become common clinical practice to combine the selective serotonin reuptake inhibitors with other serotonergic agents for augmentation or adjunctive purposes. The empirical basis for using these combinations remains limited, but is growing. Also growing is a literature that suggests that even the most apparently benign combinations of serotonergic drugs carry at least some risk of serious pharmacokinetic or pharmacodynamic drug interactions, such as a serotonin syndrome.

Abstract

This study explores the temporal relationship between anxiety and major depressive disorders in a cohort of patients with current major depression.Current prevalence and lifetime history of specific anxiety disorders were assessed using the Structured Clinical Interview for DSM-III-R Diagnosis (SCID-P) in 85 patients with DSM-III-R major depression. Consensus DSM-III-R diagnoses were assigned by at least two psychiatrists or psychologists.Twenty-nine per cent met criteria for at least one current anxiety disorder and 34% had at least one anxiety disorder at some point in their lives. The mean (s.d.) age of onset of anxiety disorder in the depressed patients with comorbid social or simple phobia (15 (9) years) was significantly younger than was that of their major depression (25 (9) years). In contrast, the mean (s.d.) age of onset of anxiety in patients with comorbid panic or OCD (20 (8) years) was similar to that seen for their major depression (21 (9) years). In patients with major depression with comorbid anxiety disorders, both the social phobia (10 of 13) and simple phobia (4 of 4) were more commonly reported to start at least two years prior to their major depression in contrast to depressives with comorbid panic (3 of 10 subjects)-Fisher's exact test, P = 0.01.Early-onset social and simple phobias appear to be risk factors for later onset of major depression.

Abstract

The co-occurrence of anxiety disorders with other mental, addictive, and physical disorders has important implications for treatment and for prediction of clinical course and associated morbidity.Cross-sectional and prospective data on 20,291 individuals from the Epidemiologic Catchment Area (ECA) study were analysed to determine one-month, current disorders, one-year incidence, and one-year and lifetime prevalence of anxiety, mood, and addictive disorders, and to identify the onset and offset of disorders within the one-year prospective period.Nearly half (47.2%) of those meeting lifetime criteria for major depression also have met criteria for a comorbid anxiety disorder. The average age of onset of any lifetime anxiety disorder (16.4 years) and social phobia (11.6 years) among those with major depression was much younger than the onset age for major depression (23.2 years) and panic disorder.Anxiety disorders, especially social and simple phobias, appear to have an early onset in adolescence with potentially severe consequences, predisposing those affected to greater vulnerability to major depression and addictive disorders.

Abstract

Mother squirrel monkeys stop carrying infants at earlier ages in high-demand (HD) conditions where food is difficult to find relative to low-demand (LD) conditions. To characterize these transitions in psychosocial development, from 10- to 21-weeks postpartum we collected measures of behavior, adrenocortical activity, and social transactions coded for initiator (mother or infant), goal (make-contact or break-contact), and outcome (success or failure). Make-contact attempts were most often initiated by HD infants, but mothers often opposed these attempts and less than 50% were successful. Break-contact attempts were most often initiated by LD infants, but mothers often opposed these attempts and fewer LD than HD infant break-contact attempts were successful. Plasma levels of cortisol were significantly higher in HD than LD mothers, but differences in adrenocortical activity were less consistent in their infants. HD and LD infants also spent similar amounts of time nursing on their mothers and feeding on solid foods. By rescheduling some transitions in development (carry-->self-transport), and not others (nursing-->self-feeding), mothers may have partially protected infants from the immediate impact of an otherwise stressful foraging task.

Abstract

We investigated the relationship between basal cortisol and dehydroepiandrosterone (DHEA) levels and impairment in different cognitive and noncognitive measures and the possible interaction of DHEA with hypercortisolemia in dementia in 27 patients diagnosed with Alzheimer's disease (AD). There were 17 men and 10 women. Patients were mildly to moderately cognitively impaired at the time of the initial cortisol measures. Patients were administered the Alzheimer's Disease Assessment Scale (ADAS) and Folstein Mini-Mental State Examination (MMSE) at approximately 6-month intervals. Cortisol and DHEA were determined using conventional 125I radioimmunoassay procedures. Pearson product-moment correlations among cortisol and DHEA measures and both initial and longitudinal clinical measures were calculated. There was a relationship between baseline 8 a.m. cortisol levels and cognitive function at the initial testing as measured by the ADAS cognitive measure, with higher cortisol levels being associated with a greater level of impairment. We did not document a relationship between cortisol or DHEA levels and noncognitive measures. There was a significant correlation between both the initial MMSE and ADAS cognitive measures and initial DHEA level, with lower DHEA levels unexpectedly being associated with better performance on these measures. The initial DHEA levels did not predict decline in cognitive function over time. These findings bring into question the potential usefulness of DHEA as a therapeutic agent.

Abstract

Serotonin selective reuptake inhibitors (SSRIs) have generally proven to be as effective as tricyclic antidepressants (TCAs) in the treatment of major depression and have an improved side effect profile. However, data suggest that the SSRIs are not as effective as the TCAs in certain subsets of depressed patients, indicating the importance of norepinephrine reuptake inhibition for such patients. Evidence for the role of norepinephrine in depression comes from early studies on excretion of catecholamines and more recent studies on receptor function, second messenger systems, and gene modification. These data are reviewed in this article. Data from a multicenter, randomized, controlled clinical trial comparing desipramine, a relatively norepinephrine-selective TCA, and the SSRI fluoxetine in moderate to marked major depression suggest a differential response depending on the antidepressant. The 2 drugs were overall similar in efficacy; however, in severely ill patients, there was a suggestion that desipramine was more likely to induce remission than fluoxetine. Urinary metabolite 3-methoxy-4-hydroxyphenylglycol levels were a better predictor of likelihood of remission than severity of episode or drug treatment. Desipramine and fluoxetine produced different longitudinal effects in catecholamine excretion, indicating that the 2 agents act through different mechanisms. Given the good therapeutic profile but relative risks associated with TCA therapy, selective norepinephrine reuptake inhibitors, such as reboxetine, which has a good safety profile, could be a major step forward in the treatment of depression.

Abstract

Recent findings in the diagnosis, classification, and epidemiology of bipolar disorder are reviewed. Specific bipolar subtypes are delineated. A number of key diagnostic issues that have implications for correctly establishing the diagnosis or for determining optimal treatment approaches are discussed. The epidemiology of comorbid substance abuse and bipolar disorder is reviewed as is the significance of this comorbidity vis-à-vis presenting symptoms, treatment, and outcome. The differential diagnosis between so-called mixed states and agitated depressed is reviewed, and the potential significance of comorbid bipolar disorder and attention-deficit/hyperactivity disorder is discussed.

Abstract

EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia.A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study.Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions.Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events.EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.

Abstract

Adverse events following discontinuation from serotonin reuptake inhibitors (SRIs) are being reported in the literature with increasing frequency; the frequency and severity of these symptoms appear to vary according to the half-life of the SRI, e.g., the incidence appears higher with the shorter half-life agents than with fluoxetine, which has an extended half-life. Yet, there have been no systematic studies of the phenomenon to date. Therefore, a group of experts convened in Phoenix, Arizona, to develop a clear description or definition of the phenomenon based on these reports. The SRI discontinuation syndrome, referred to as "withdrawal symptoms" in many anecdotal case reports, is distinctly different from the classic withdrawal syndrome associated with alcohol and barbiturates. Anti-depressants are not associated with dependence or drug-seeking behavior. SRI discontinuation symptoms tend to be short-lived and self-limiting, but can be troublesome. They may emerge when an SRI is abruptly discontinued, when doses are missed, and less frequently, during dosage reduction. In addition, the symptoms are not attributable to any other cause and can be reversed when the original agent is reinstituted, or one that is pharmacologically similar is substituted. SRI discontinuation symptoms, in most cases, may be minimized by slowly tapering antidepressant therapy, but there have been several case reports where symptoms occurred consistently even through repeated attempts to taper therapy. Physical symptoms include problems with balance, gastrointestinal and flu-like symptoms, and sensory and sleep disturbances. Psychological symptoms include anxiety and/or agitation, crying spells, and irritability. Further analyses of data bases and clinical studies are needed to define this proposed syndrome more clearly.

Abstract

Although the number of documented serotonin reuptake inhibitor (SRI) discontinuation reactions is increasing, to date no systematic studies have been completed; therefore the mechanism of action for these reactions is not clearly understood. However, several hypotheses have been proposed. Researchers have postulated that discontinuation events result from a sudden decrease in the availability of synaptic serotonin in the face of down-regulated serotonin receptors. In addition, other neurotransmitters, such as dopamine, norepinephrine, or gamma-aminobutyric acid (GABA), may also be involved, although little research in this area has been published. Individual patient sensitivity, i.e., genetics or cognitive mindset, may also be a factor in SRI discontinuation phenomena. Finally, experts have hypothesized that since some symptoms associated with paroxetine withdrawal are similar to those of tricyclic antidepressant discontinuation, they may be caused by cholinergic rebound.

Abstract

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population.

Abstract

Clinical data and uncontrolled observations have suggested that fluoxetine is helpful in some patients with borderline personality disorder. This article describes the results of a 13-week double-blind study of volunteer subjects with mild to moderately severe borderline personality disorder. Thirteen fluoxetine recipients and nine placebo recipients received treatment. Pretreatment and posttreatment measures were obtained for global mood and functioning, anger, and depression. The most striking finding from this study was a clinically and statistically significant decrease in anger among the fluoxetine recipients. This decrease was independent of changes in depression. These data support previous observations that fluoxetine may reduce anger in patients with borderline personality disorder. The number of subjects in this study was small, the placebo responsiveness was high, and the clinical characteristics of the patients were in the mild to moderate range of severity. The data cannot be extrapolated to more severely ill borderline patients, but further study of fluoxetine and other selective serotonin reuptake inhibitors is indicated in this population.

Abstract

The efficacy and safety of fluoxetine and desipramine were compared in a 6-week double-blind, parallel group study of patients with major depression. Twenty-five were studied while hospitalized for treatment, and 33 were studied as outpatients. Improvement on the Hamilton Rating Scale for Depression was significant for both treatments from week 1 through the end of the study and did not differ between the two treatments at any week. Overall, 64% of fluoxetine-treated patients and 68% of desipramine-treated patients had at least a 50% reduction in Hamilton Depression score. We assessed whether improvement relatively early in treatment was predictive of categorical response at 6 weeks. Among fluoxetine-treated patients, but not desipramine-treated patients, the week 3 change in the Hamilton Depression mood item was significantly predictive of the response at 6 weeks. Patients treated with fluoxetine had significantly fewer side effects than those treated with desipramine. Desipramine, but not fluoxetine, caused a persistent increase in heart rate. The results suggest that early signs of response to fluoxetine are not dependent on achieving steady-state levels of the drug.

Abstract

Therapeutic efficacy for depression and panic disorder has been demonstrated with the triazolobenzodiazepine alprazolam. However, potentially serious adverse events, including depression and suicide attempts, have been reported in patients taking this medication. In this paper, reports addressing the association between each of these two events and benzodiazepine use in general and, more specifically, alprazolam use, are reviewed. We conclude that while these adverse events do occur in patients taking alprazolam, the causal relationship remains unclear and requires further study. Fortunately, these events are observed only rarely, so the prudent clinician may continue to safely prescribe this useful medication.

Abstract

The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

Abstract

Psychotic (delusional) major depression is a distinct syndrome with marked morbidity. Previous studies have emphasized the role that glucocorticoids and dopamine may play in the pathogenesis of the disorder as well as in its response to treatment. In addition to reviewing data on these two systems, the possible role serotonin (5-HT) may play is also reviewed. Studies indicate increased 5-HT reuptake into platelets and elevated cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) are found in patients with this disorder. In addition, amoxapine, a four-ringed antidepressant with 5-HT2 antagonistic properties, has been reported to be effective in treating patients with this disorder. The implications of these findings vis-à-vis a role for serotonin in delusional major depression are discussed. Future studies on serotonin as well as on 5-HT2 antagonists in delusional depression are warranted.

PSYCHOTIC (DELUSIONAL) MAJOR DEPRESSION - SHOULD IT BE INCLUDED AS A DISTINCT SYNDROME IN DSM-IVAMERICAN JOURNAL OF PSYCHIATRYSchatzberg, A. F., Rothschild, A. J.1992; 149 (6): 733-745

Abstract

To review data supporting or not supporting the designation of unipolar psychotic major depression as a distinct syndrome in DSM-IV, the authors used computerized literature searches to identify reports of studies that have directly compared the characteristics, biology, familial transmission, course/outcome, and response to treatment of psychotic and nonpsychotic major depression. The review showed that statistically significant differences between the two types of depression have been found on each of these dimensions. There are greater guilt feelings and psychomotor disturbance, among other features, in psychotic depression. Studies have found significant differences between patients with psychotic and nonpsychotic depression in glucocorticoid activity, dopamine beta-hydroxylase activity, levels of dopamine and serotonin metabolites, sleep measures, and ventricle-to-brain ratios. Family studies show higher rates of bipolar disorder in first-degree relatives of probands with psychotic major depression than of probands with nonpsychotic major depression. Greater morbidity and residual impairment have also been reported in patients with psychotic major depression, and they respond more poorly to placebo and to tricyclic antidepressants. Differences between patients with psychotic and nonpsychotic major depression on many of these measures were not due to differences in severity or endogenicity. Since the data indicate that psychotic and nonpsychotic major depression can be separated, the frequency with which the diagnosis of psychotic major depression is missed and its unique course and response to treatment point to the practical importance of a separate diagnosis for this disorder. However, further studies are needed to resolve important methodological issues and to develop an optimal set of operational criteria.

Abstract

Pretreatment 24 hr urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the Depression-type (D-type) scores (derived from a multivariate discriminant function equation based on levels of urinary catecholamines and metabolites) were examined as possible predictors of antidepressant responses to either imipramine or alprazolam. In the case of imipramine, the responders had significantly lower pretreatment urinary MHPG levels (p = 0.002) and D-type scores (p less than 0.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p less than 0.05) and D-type scores (p = 0.02) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. For each drug, the effect size for the difference in mean log-transformed D-type scores between responders and nonresponders was greater than the effect size for the difference in mean log-transformed MHPG levels. The difference between the effect sizes was statistically significant for imipramine (p = 0.02) and tended toward significance for alprazolam using two-tailed tests. These results suggest that the D-type equation, which was initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, can also be used to predict differential responses to certain antidepressant drugs in patients with unipolar depressions.

DECISIONS FOR THE CLINICIAN IN THE TREATMENT OF PANIC DISORDER - WHEN TO TREAT, WHICH TREATMENT TO USE, AND HOW LONG TO TREATSYMP ON PANIC DISORDER : STRATEGIES FOR LONG-TERM TREATMENT / 1990 ANNUAL MEETING OF THE AMERICAN PSYCHIATRIC ASSOCSchatzberg, A. F., Ballenger, J. C.PHYSICIANS POSTGRADUATE PRESS.1991: 26–31

Abstract

Issues in clinicians' decisions about initiation, selection, and duration of treatment for patients with panic disorder are reviewed. Panic disorder may entail considerable morbidity, particularly if left untreated. This observation, coupled with clinical experience that the benefits of pharmacologic treatment generally outweigh their risks, suggests that patients with panic disorder should be treated with medication. A decision tree for the acute and maintenance treatment of panic disorder patients is presented, and possible indications for both acute and maintenance treatments are discussed. The advantages and disadvantages of treatment with each of the three classes of drugs that have been found effective for panic disorder--the tricyclic antidepressants, the monoamine oxidase inhibitors, and the benzodiazepines--are reviewed.

Abstract

Methodologic issues pertinent to the study of depression secondary to anxiety are reviewed. Data on the frequency and temporal sequence of comorbid DSM-III-R anxiety and depressive disorders in a sample from the McLean Hospital Depression Research Facility are presented. Patients with major depression secondary to anxiety are compared with major depressed patients without anxiety on a variety of demographic and clinical variables. Conceptual and practical frameworks are developed for assessing and understanding comorbidity and secondary depression.

Abstract

A patient who developed chronic bipolar disorder following mitral valvuloplasty is presented. A brief review of literature is offered to compare functional bipolar disorder with those of organic etiology and to elucidate the role of brain and blood-flow imaging studies.

Abstract

Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.

Abstract

A 12-week open study was conducted to assess the possible efficacy and safety of low-dose thioridazine in 11 outpatients (8 women, 3 men) with borderline personality disorder (BPD) diagnosed according to DSM-III-R (American Psychiatric Association 1987) and the Diagnostic Interview for Borderline Patients (DIB; Gunderson et al. 1981) criteria. Mean thioridazine dose averaged 92 mg per day across the duration of this study. At endpoint, there was a significant reduction in Brief Psychiatric Rating Scale (BPRS; Overall & Gorham 1988) scores, and patients appeared to be less symptomatic on the impulse action patterns, affects, and psychosis subscales of the DIB (modified to assess change). Subjects completing the entire study (n = 6) also showed improvement in interpersonal relations. On self-report measures, significant improvement was noted on most Hopkins Symptom Checklist-90 (SCL-90; Derogatis et al. 1973) subscales, particularly in hostility and additional depressive features. Subjects completing the entire study showed significant improvement in paranoid ideation, interpersonal sensitivity, and anxiety. Three patients, however, developed sustained melancholic depressions that necessitated their discontinuation from the study and the initiation of anti-depressant treatment. These three individuals were more schizotypal, schizoid, and paranoid at baseline according to Personality Disorder Examination (PDE; Loranger et al. 1987) structured interviews. Weight gain was not a significant problem, but sedation and erectile dysfunction were. Overall, these findings suggest that thioridazine may exert prominent effects on patients with BPD and that double-blind, placebo-controlled studies are warranted.

Abstract

The present study examined the relationship between 24-hr urinary catecholamine (norepinephrine and epinephrine) output and measures of platelet adenylate cyclase (AC) activity in depressed patients (n = 17) and control subjects (n = 10). In both groups, significant inverse correlations were observed when 24-hr urinary catecholamine levels were examined in relation to measures of both receptor-mediated (prostaglandin D2 and alpha 2-adrenergic) and postreceptor-mediated (NaF) platelet AC enzyme activities, suggesting that circulating catecholamines may regulate platelet AC by heterologous (agonist-nonspecific) desensitization of the AC enzyme complex. Depressed patients who had favorable antidepressant responses to alprazolam had significantly higher pretreatment urinary catecholamine output and lower receptor-mediated platelet AC enzyme activities than control subjects, whereas the nonresponders did not. After 8 days of treatment with alprazolam, urinary catecholamine levels declined significantly. In responders, receptor-mediated measures of platelet AC activity increased significantly by day 8 to values comparable to those in control subjects; but similar changes were not observed in nonresponders. Prior to treatment, responders showed a strict linear relationship between receptor-mediated (prostaglandin D2) and postreceptor-mediated (NaF) stimulation of platelet AC activity through the stimulatory guanine nucleotide regulatory protein (Ns), whereas nonresponders did not. This suggests the presence of two distinct coupling interactions between platelet prostaglandin D2 receptors and the stimulatory guanine nucleotide regulatory protein in responders and nonresponders to the antidepressant effects of alprazolam prior to treatment. The authors propose that catecholamines, possibly acting through prostaglandins, may regulate platelet AC enzyme activity by heterologous desensitization occurring through postreceptor mechanisms.

Abstract

In recent years, the role of serotonin in the pathophysiology of depressive disorders has been intensively studied. These studies have been complemented by the development of newer antidepressant agents that exert specific effects on serotonin systems. This paper reviews the pharmacology of these newer compounds and contrasts it with those of the standard tricyclic antidepressants. The current status of various serotonergic agents is discussed. Results are reviewed from recent double-blind studies comparing three compounds (trazodone, fluoxetine, and fluvoxamine) to a standard tricyclic antidepressant. Relative efficacy, dropout rates, optimal dosages, and side effects are emphasized. Data from studies on trazodone and fluoxetine suggest that lower dosages may prove as effective (if not more effective) than very high dosages. Implications of these data are discussed. Side effects of fluoxetine and fluvoxamine include primarily nausea, weight loss, insomnia, and anxiety. Possible application of specific serotonin reuptake blockers in the treatment of obsessive-compulsive disorder and in the reduction of alcohol consumption is also reviewed.

Abstract

Unconjugated plasma catecholamines and cortisol were measured before and after a 1 mg dose of dexamethasone in 22 medication-free depressed patients and 6 healthy, medication-free control subjects. Plasma dopamine (DA) levels in the psychotically depressed subgroup (n = 4) were significantly higher both before and after dexamethasone than those in the nonpsychotic depressed group and higher before dexamethasone than in the control group. Similarly, the psychotically depressed group exhibited significantly higher cortisol levels both before and after dexamethasone than the nonpsychotic depressed group or the control group. In contrast, the psychotically depressed group had significantly lower postdexamethasone plasma norepinephrine levels compared to the nonpsychotic depressed group. In both patients and controls, plasma DA was significantly higher after dexamethasone administration than before, but the magnitude of the increase was 10 times greater in controls than in patients.

Abstract

Preliminary data are presented on levels of plasma cortisol, dopamine (DA), epinephrine (EPI), and norepinephrine (NE) before and after dexamethasone in 22 depressed patients (of whom 4 were psychotic). Platelet monoamine oxidase (MAO) activity, determined in 19 of the depressed patients, was significantly higher in the 4 psychotic patients than it was in the 15 nonpsychotic patients. Positive correlations were observed before and after dexamethasone among cortisol, DA, EPI, and platelet MAO. After dexamethasone, plasma NE correlated negatively with DA, EPI, and cortisol. The various correlations were due largely to the inclusion of the psychotic depressive subgroup. Data are also presented on the relationships between these biological measures and specific signs and symptoms.

Abstract

Results of the Dexamethasone Suppression Test (DST), performed on 65 patients with major unipolar depression, were classified both by suppression versus nonsuppression and by three ranges of postdexamethasone cortisol levels. Subgroups of patients were then compared for familial prevalence for depression and alcoholism and for delusional symptomatology. A strong association emerged among high postdexamethasone cortisol levels, a significantly increased familial prevalence for depression, and the presence of delusions in probands. In this study, ranges of DST responses were superior to suppression versus nonsuppression criteria alone in defining this subgroup.

Abstract

Eleven McLean Hospital (Belmont, Mass) depressed patients who experienced seizures while receiving maprotiline hydrochloride are presented, as are data on 87 cases reported to the manufacturer (Ciba-Geigy). Most seizures occurred at high dosages, sometimes after many weeks at a stable dose, but neither rapid dosage escalation nor high drug plasma levels seemed related to seizure occurrence. Our experience suggests that a long-acting metabolite might be responsible for seizures. Ten of the 11 McLean Hospital seizures occurred in patients receiving dosages outside of the since-revised current dosage guidelines, as did 60% of the seizures reported to the company. Data in this study suggest that reductions in maximum dosage of maprotiline prescribed after the initial six weeks of treatment could result in a further decrease in risk of seizures beyond that obtained from previous alterations in regimens.

Abstract

In recent years, considerable data have emerged that psychotic (delusional) depression is characterized by pronounced increases in hypothalamic-pituitary-adrenal (HPA) axis activity and positive responses to combined treatment with tricyclic antidepressants and antipsychotic (dopamine-blocking) agents. Recently, a number of observations in several species, including man, point to glucocorticoids' increasing dopamine activity in a variety of tissues and this effect is particularly marked in rat brain mesolimbic dopamine systems. We propose that glucocorticoids' enhancement of dopaminergic activity may explain the development of psychosis/delusions in the context of the depressive episode. Data in support of the hypothesis are presented and the identification of possible enzymatic risk factors are discussed. These interactions also have implications for understanding the biology of corticosteroid-induced psychoses in medical patients and some of the psychiatric complications of Cushing's Disease.

Abstract

Post-dexamethasone cortisol and platelet monoamine oxidase (MAO) activity levels were examined in 50 depressed patients. The incidence of non-suppression was significantly greater in patients with high platelet MAO activity than in those with low activity. Similar results were obtained when males and females were analysed separately. The mean 4 p.m. post-dexamethasone cortisol level was significantly higher in those patients who had high MAO activity than in their low MAO counterparts. Moreover, a statistically significant positive correlation was observed between platelet MAO activity and 4 p.m. post-dexamethasone cortisol levels.

Abstract

The triazolobenzodiazepine, alprazolam, was administered to 11 depressed patients over a period of six weeks, and six patients showed a favorable antidepressant response. There were no significant differences between responders and nonresponders in age, pretreatment Hamilton Depression Rating Scores, 4 p.m. postdexamethasone plasma cortisol levels, or platelet monoamine oxidase activities. Blood levels of alprazolam were not meaningfully different in responders and nonresponders when measured on treatment day 8. However, on treatment day 8, significantly enhanced prostaglandin D2-stimulated platelet adenylate cyclase activity, greater suppression of prostaglandin D2-stimulated platelet adenylate cyclase activity by epinephrine, and enhanced sodium fluoride-stimulated platelet adenylate cyclase activity were seen in the six patients who went on to respond to alprazolam, but not in the five nonresponders. In contrast, there were no significant changes in prostaglandin D2, (-)-isoproterenol, or fluoride ion-stimulated leukocyte adenylate cyclase activity in responders or nonresponders. No meaningful changes were observed in the mean densities of either the high-affinity platelet alpha 2-adrenergic receptor (for 3H-p-aminoclonidine) or the leukocyte beta-adrenergic receptor (for 3H-dihydroalprenolol) in responders or nonresponders. The present findings, taken in conjunction with findings from other recent studies, suggest that enhanced coupling between certain neurotransmitter or hormone receptors and adenylate cyclase through the guanine nucleotide regulatory proteins may help explain the antidepressant effects of alprazolam and possibly other forms of antidepressant treatment.

Abstract

Platelet monoamine oxidase (MAO) activity was examined in 77 depressed patients (40 males and 37 females) and 28 controls (14 males and 14 females). Patients were compared across increasingly specific diagnostic groupings in a four-step data analytic procedure. In step 1, MAO activity in the total sample of depressed patients was compared with that of control subjects. In step 2, Unipolar depressed patients were compared with Bipolar (Bipolar I and Bipolar II) depressed patients. In step 3, Unipolar depressed patients with and without schizotypal features were compared. In step 4, both the nonschizotypal Unipolar patients and compared. In step 4, both the nonschizotypal Unipolar patients and nonschizotypal Bipolar patients were separated into those who met RDC criteria for a definite Endogenous depression and those who did not; and platelet MAO activity was compared in the resulting four groups. Results indicated significantly higher platelet MAO activity in nonschizotypal Unipolar Endogenous depressed patients than in nonschizotypal Bipolar Endogenous depressed patients or nonschizotypal Unipolar Other patients. In addition, the presence of a definite Endogenous depressive syndrome was associated with greater overall symptom severity in both Unipolar and Bipolar depressed patients. Findings are discussed with respect to the conflicting results reported in previous studies of MAO activity in patients with depressive disorders.

Abstract

The authors present preliminary data showing that pretreatment levels of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly higher in six depressed patients who responded to the antidepressant effects of alprazolam than in six depressed patients who showed no antidepressant response.

Abstract

Twenty male Sprague-Dawley rats were injected intraperitoneally with either 20 micrograms of dexamethasone or an equivalent volume of saline. The rats were then sacrificed at either one or four hours after the injections and their brains analyzed for monoamine and metabolite content using High Performance Liquid Chromatography with Electrochemical Detection. Significant effects were seen in dopaminergic and serotonergic systems, but these effects varied depending on the area of rat brain studied. Significant increases in dopamine (DA) levels were seen in the hypothalamus and nucleus accumbens of the dexamethasone treated rats when compared with saline treated rats. There was no significant effect of dexamethasone on DA levels in frontal or striatal brain areas. In the dexamethasone treated rats a significant increase in serotonin (5-HT) was observed in the hypothalamus; a significant decrease in 5-HT was observed in the frontal cortex. Biological and clinical implications of these findings are discussed.

Abstract

In man, unconjugated plasma DA is normally undetectable or present in minute amounts. Twelve medication-free volunteers received a 1 mg dose of dexamethasone which produced pronounced increases of plasma free DA but not of other catecholamines. Mean plasma free dopamine levels after dexamethasone at 8 a.m. (155 +/- 102 pg/ml) and 4 p.m. (163 +/- 70 pg/ml) were significantly higher (p less than 0.001) than those at 8 a.m. (50 +/- 18 pg/ml) and 4 p.m. (42 +/- 7 pg/ml) before dexamethasone. Although the mechanism of increased dopaminergic activity after a dose of dexamethasone remains for future research, the data presented in this paper may explain the observations that corticosteroids lower prolactin levels and may induce psychiatric disturbances, as well as the finding that depressed patients with high postdexamethasone cortisol levels are frequently psychotic.

Abstract

he authors used competitive protein binding assay and radioimmunoassay to measure cortisol levels in 38 normal control subjects three times before and three times after administration of 1 mg of dexamethasone. They found significant interassay differences at 11:00 p.m. before dexamethasone and at all three postdexamethasone times. Analysis of variance revealed significant overall positive relationships between age and cortisol levels measured by both techniques. Age correlated significantly with postdexamethasone cortisol levels measured by radioimmunoassay but not when measured by competitive protein binding assay. Clinicians should obtain data from their laboratories as to appropriate cutoffs for cortisol suppression on the specific assay used.

Abstract

To investigate the specificity of the dexamethasone suppression test (DST) for the diagnosis of major depression in patients with diabetes mellitus, we administered 1 mg of dexamethasone to 30 nondepressed diabetics and to 58 normal controls at 11 PM. Diabetic subjects received hemoglobin A1 (Hb A1) determinations, the Hamilton Rating Scale for Depression (HRSD), and five to eight blood glucose determinations during the 48 hours surrounding the DST. Results demonstrated a significantly higher rate of nonsuppression (plasma cortisol level, greater than or equal to 5 micrograms/dL) at 4 PM the following day among diabetics (43%) than among controls (7%) but no difference between these groups in the rate of nonsuppression at 8 AM. Plasma cortisol level at 4 PM correlated with Hb A1 level but not with duration of illness, HRSD score, mean blood glucose level, or maximum blood glucose excursion. These results suggest that the results of the DST used as a diagnostic test for major depression must be interpreted with caution in patients with diabetes.

Abstract

Platelet monoamine oxidase (MAO) activity and postdexamethasone cortisol levels were determined in 26 depressed patients. The incidence of cortisol nonsuppression and the mean postdexamethasone cortisol levels were significantly higher in patients with high MAO activity than in those with low MAO activity.

Abstract

The authors measured urinary free cortisol and urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in 24 severely depressed patients and 22 normal control subjects. Urinary free cortisol levels were significantly higher in the depressed patients than in the control subjects, but mean urinary MHPG levels were not significantly different in these two groups. A very high positive correlation between urinary MHPG levels and urinary free cortisol levels was found in the depressed patients but not in the control subjects.

Abstract

The authors found that the mean urinary level of 3-methoxy-4-hydroxyphenylglycol (MHPG) was significantly lower in 20 patients with bipolar manic-depressive or schizoaffective depressions than in either 50 patients with unipolar depressions or 26 age- and sex-matched control subjects. In contrast, the mean MHPG levels in the total group of patients with unipolar depressions and in any subgroup defined by Research Diagnostic Criteria (RDC) were not significantly different from control values. However, examination of the distribution of urinary MHPG levels in patients with unipolar depressions in relation to other recent findings by the authors' collaborative research group suggested the existence of at least three biochemical subtypes of unipolar depressions that may, in part, be differentiated on the basis of urinary MHPG levels.

Abstract

Plasma cortisol levels examined at 16.00 hours after dexamethasone in 31 controls and in 34 psychotic patients with various diagnoses, suggests that the ranges of such levels may help to discriminate among subtypes of psychotic patients. They were significantly higher in the unipolar depressed psychotic group than in control subjects or in psychotic patients with bipolar depression or schizophrenia. Moreover, the distribution of values differed between groups. Whereas 8 of 14 psychotic patients with unipolar depressive illness had post-dexamethasone cortisol values greater than or equal to 14 micrograms/dl, none of the remaining psychotic patients had similarly high values. Implications of these data are discussed.

Abstract

Pretreatment urinary MHPG levels were examined in 28 depressed patients as a possible predictor of response to treatment with maprotiline, a tetracyclic antidepressant that exerts potent effects on norepinephrine uptake, but has little effect on serotonin uptake. Maprotiline was administered in doses up to 150 mg/day during the first 2 weeks after which time the dose could be increased incrementally up to 300 mg/day if indicated clinically. At 2 weeks, patients with low pretreatment urinary MHPG levels responded more favorably to treatment than did patients with high MHPG levels. At 4 weeks, patients with low MHPG levels continued to show more favorable responses; however, differences between the two groups were less clear-cut than at 2 weeks. The findings suggest the patients with low pretreatment urinary MHPG levels are more sensitive to, and respond more rapidly to, treatment with maprotiline than patients with high pretreatment urinary MHPG levels.

Abstract

This article summarizes findings from a series of studies that examined platelet monoamine oxidase (MAO) activity in patients with nonaffective schizophrenic disorders and schizophrenia-related depressions. The findings indicate that mean platelet MAO activity was not different from control values in the subgroup of nonaffective schizophrenic disorders without auditory hallucinations (that is, the S-1 subgroup). However, mean platelet MAO activity was reduced in the subgroup of nonaffective schizophrenic disorders characterized by the presence of auditory hallucinations often occurring in conjunction with paranoid features (that is, the S-2 subgroup). Moreover, we found that mean platelet MAO activity was increased in schizophrenia-related depressions characterized by histories of chronic asocial, eccentric, or bizarre behavior.

Abstract

The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) and other catecholamine metabolites was measured in a series of 63 patients with various clinically defined subtypes of depressive disorders. MHPG excretion was significantly lower in patients with bipolar manic-depressive depressions and schizo-affective depressions than in patients with unipolar nonendogenous depressions. Patients with schizophrenia-related depressions also excreted reduced levels of MHPG when compared with patients with unipolar nonendogenous depressions. Moreover, levels of urinary epinephrine and metanephrine were significantly lower in patients with schizophrenia-related depressions. These data, coupled with our recent finding that patients with schizophrenia-related depressions had significantly higher levels of platelet monoamine oxidase activity than control subjects of patients with unipolar endogenous depressions, suggest that we can discriminate three biochemically discrete subgroups of depressive disorders corresponding to the following clinically defined subtypes: (1) the bipolar manic-depressive depressions plus the schizo-affective depressions; (2) the unipolar nonendogenous depressions; and (3) the schizophrenia-related depressions.

Abstract

Some investigators have found benzodiazepines effective in the treatment of anxious depression and thus have argued that benzodiazepines were "antidepressants." We reviewed the literature on benzodiazepines in depressive disorders. Comparative studies indicate they are less effective than standard antidepressants in the treatment of several types of depressive illnesses. Although they display definite anxiolytic properties and may elevate mood, they exert limited effect on the core symptoms of endogenous depression. An argument is made that benzodiazepines are primarily anxiolytic rather than antidepressant.

Abstract

The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders.

Abstract

Platelet monoamine oxidase (MAO) activity was measured in patients with nonaffective schizophrenic disorders (i.e., without prominent symptoms of depressions or manias), and in patients with schizophrenia-related depressions. MAO activity was significantly lower than control values in a subgroup of 16 patients with nonaffective schizophrenic disorders (most of whom were paranoid) characterized by the presence of auditory hallucinations and delusions. Platelet MAO activity was not reduced in 16 other nonaffective schizophrenic patients without auditory hallucinations. Platelet MAO activity was significantly higher than control values in a group of 8 depressed patients with schizophrenia-related depressions characterized by the presence of chronic asocial, eccentric, or bizarre behavior. These findings of differences in platelet MAO activity in clinically defined subgroups of nonaffective schizophrenic disorders and the schizophrenia-related depressive disorders may help to account for some of the discrepancies in findings among the various studies of platelet MAO activity in schizophrenic and affective disorders.

Abstract

The findings summarized in this paper show that norepinephrine turnover in brain is decreased after acute administration of imipramine or desmethylimipramine but tends to increase during chronic administration of these tricyclic antidepressants. Similarly, it appears that there also may be important differences between the effects of acute and chronic administration of lithium salts on norepinephrine turnover in the central nervous system. Such changes in norepinephrine turnover that develop gradually over the course of long-term drug administration may help to explain the need for chronic administration of tricyclic antidepressants or lithium salts in the treatment of patients with affective disorders.